Compounds for the treatment of inflammatory disorders

ABSTRACT

This invention relates to compounds of the Formula (I):                  
 
or a pharmaceutically acceptable salt, solvate or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, TNF-α or combinations thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of patent application Ser. No.10/323,511, filed Dec. 19, 2002, now U.S. Pat. No. 6,838,466 whichclaims the benefit of priority from U.S. Provisional Patent ApplicationSer. No. 60/342,332, filed Dec. 20, 2001, both incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to hydroxamic or carboxylic acid functionalcompounds that can inhibit the production of tumor necrosis factor alpha(TNF-α), pharmaceutical compositions comprising such compounds, andmethods of treatment using such compounds.

2. Description

Tumor necrosis factor alpha (TNF-α) has been shown to play a pivotalrole in immune and inflammatory responses. Inappropriate orover-expression of TNF-α is a hallmark of a number of diseases,including rheumatoid arthritis (RA), Crohn's disease and sepsis.Inhibition of TNF-α production has been shown to be beneficial in manypreclinical models of inflammatory disease, making inhibition of TNF-αproduction or signaling an appealing target for the development of novelanti-inflammatory drugs.

Tumor necrosis factor alpha is a cell-associated cytokine that isprocessed from a 26 kd precursor form to a 17 kd active form. See BlackR. A. “Tumor necrosis factor-alpha converting enzyme” Int J Biochem CellBiol. 2002 January; 34(1):1–5 and Moss M L, White J M, Lambert M H,Andrews R C.“TACE and other ADAM proteases as targets for drugdiscovery” Drug Discov Today. 2001 Apr. 1; 6(8):417–426, each of whichis incorporated by reference herein.

TNF-α has been shown to be a primary mediator in humans and animals ofinflammation, fever and acute phase responses, similar to those observedduring acute infection and shock. Excess TNF-α has been shown to belethal. Blocking the effects of TNF-α with specific antibodies can bebeneficial in a variety of conditions, including autoimmune diseasessuch as rheumatoid arthritis (Feldman et al, Lancet, (1994) 344, 1105),non-insulin dependent diabetes mellitus (Lohmander L. S. et al.,Arthritis Rheum. 36 (1993) 1214–22) and Crohn's disease (Macdonald T. etal., Clin. Exp. Immunol. 81 (1990) 301).

Metalloproteinases (MP) are important in the uncontrolled breakdown ofconnective tissue, including proteoglycan and collagen, leading toresorption of the extracellular matrix. This is a feature of manypathological conditions, such as rheumatoid and osteo-arthritis,corneal, epidermal or gastric ulceration; tumor metastasis or invasion;periodontal disease and bone disease. Normally these catabolic enzymesare tightly regulated at the level of their synthesis as well as attheir level of extracellular activity through the action of specificinhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor ofmetalloproteinase), which form inactive complexes with the MP's.

Osteo- and rheumatoid arthritis (OA and RA, respectively) aredestructive diseases of articular cartilage characterized by localizederosion of the cartilage surface. Findings have shown that articularcartilage from the femoral heads of patients with OA, for example, had areduced incorporation of radiolabeled sulfate over controls, suggestingthat there must be an enhanced rate of cartilage degradation in OA(Mankin et al. J. Bone Joint Surg. 52A (1970) 424–434). There are fourclasses of protein degradative enzymes in mammalian cells: serine,cysteine, aspartic and metalloproteinases. The available evidencesupports that it is the metalloproteinases that are responsible for thedegradation of the extracellular matrix of articullar cartilage in OAand RA. Increased activities of collagenases and stromelysin have beenfound in OA cartilage and the activity correlates with severity of thelesion (Mankin et al. Arthritis Rheum. 21, 1978, 761–766, Woessner etal. Arthritis Rheum. 26, 1983, 63–68 and Ibid. 27, 1984, 305–312). Inaddition, aggrecanase (a newly identified metalloproteinase enzymaticactivity) has been identified that provides the specific cleavageproduct of proteoglycan, found in RA and OA patients (Lohmander L. S. etal. Arthritis Rheum. 36, 1993, 1214–22).

Therefore, metalloproteinases (MP) have been implicated as the keyenzymes in the destruction of mammalian cartilage and bone. It can beexpected that the pathogenesis of such diseases can be modified in abeneficial manner by the administration of MP inhibitors, and manycompounds have been suggested for this purpose (see Wahl et al. Ann.Rep. Med. Chem. 25, 175–184, AP, San Diego, 1990).

Compounds that inhibit the production of TNF-α are therefore oftherapeutic importance for the treatment of inflammatory disorders.Recently it has been shown that a matrix metalloproteinase (MMP) orfamily of metalloproteinases, hereafter known as TNF-α convertases(TACE), as well as other MP's are capable of converting TNF-α from itsinactive to active form (Gearing et al Nature, 1994, 370, 555). Sinceexcessive TNF-α production has been noted in several disease conditionsalso characterized by MMP-mediated tissue degradation, compounds whichinhibit both MMPs and TNF-α production may also have a particularadvantage in diseases where both mechanisms are involved.

There are several patents which disclose hydroxamate and carboxylatebased MMP inhibitors.

W095/09841 describes compounds that are hydroxamic acid derivatives andare inhibitors of cytokine production.

European Patent Application Publication No. 574,758 A1, discloseshydroxamic acid derivatives as collagenase inhibitors. GB 2 268 934 Aand WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors ofTNF-α production.

There is a need in the art for inhibitors of MMPS, in particular TNF-αconvertase, which can be useful as anti-inflammatory compounds andcartilage protecting therapeutics. The inhibition of TNF-α convertaseand other metalloproteinases can prevent the degradation of cartilage bythese enzymes, thereby alleviating the pathological conditions of osteo-and rheumatoid arthritis.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a compound representedby Formula (I):

or a pharmaceutically acceptable salt, solvate or isomer thereof,wherein:

M is —(C(R³⁰)(R⁴⁰)_(m)—, wherein m is 1 to 6;

T is selected from the group consisting of R²¹-substituted alkyl,cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl,heteroaryl, —OR³, —C(O)R⁴, —C(O)OR³, —C(O)NR²⁴R²⁵, —C(O)NR²⁴OR³,—C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵,—NR²⁵C(O)NR²⁴OR³, —SR³, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN,—P(O)(R²⁴)(OR²⁴), —P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)-AA-NR²⁴R²⁵and —C(O)-AA-NR²⁵OR³,

wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of T is independentlyunsubstituted or substituted with one to five independently selected R²⁰moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties below;

V is selected from the group consisting of alkyl, R²¹-substituted alkyl,cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl,heteroaryl, —OR³, —C(O)R⁴, —(CR²³R²⁴)_(n1)C(O)OR³, —C(O)NR²⁴R²⁵,—(CR²³R²⁴)_(n1)C(O)NR²⁵OR³, —C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴,—NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵, —NR²⁵C(O)NR²⁴OR³, —SR³,—S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN, —P(O)(R²⁴)(OR²⁴),—P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)-AA-NR²⁴R²⁵ and—C(O)-AA-NR²⁵OR₃,

wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of V is independentlyunsubstituted or substituted with one to three independently selectedR²⁰ moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties below;

W is selected from the group consisting of

a covalent bond, —(C(R³)(R⁴))_(n2)—, —O—, —S—, and —N(Z)-;

X is selected from the group consisting of alkylene, cycloalkylene,heterocycloalkylene, arylene, heteroarylene and —C≡C—, wherein each ofthe alkylene, cycloalkylene, heterocycloalkylene, arylene orheteroarylene groups of X is independently unsubstituted or substitutedwith one to four independently selected R²⁰ moieties which can be thesame or different, each R²⁰ moiety being independently selected from thegroup of R²⁰moieties below;

U is selected from the group consisting of a covalent bond,—(C(R³)(R⁴))_(p)—, —Y—(C(R³)(R⁴))_(q)—, —(C(R³)(R⁴))_(t)—Y—, and —Y—;

Y is selected from the group consisting of —O—, —S(O)_(x)—, —N(Z)-,—C(O)—, —OC(O)—, —C(O)N(R²⁴)—, —N(R²⁴)C(O)N(R²⁵)—, —N(R²⁴)S(O)—,N(R²⁴)S(O)₂—, —S(O)N(R²⁴)—, and —S(O)₂N(R²⁴)—;

Z is selected from the group consisting of —R³, —C(O)R³, —S(O)_(x)R³ and—C(O)NR³R⁴;

n is 0 to 2;

n1 is 0 to 2;

n2 is 1 to 2;

p is 1 to 4;

q is 1 to 4;

t is 1 to 4;

v is 1 to 3;

x is 0 to 2;

y is 0 to 3;

AA is

wherein R³¹ and R³² are the same or different and are each independentlyselected from the group consisting of H, alkyl, cycloalkyl, aryl,heteroaryl, —NR²⁴R²⁵, —(CH₂)₃NH(C═NH)NH₂, —CH₂C(O)NH₂, —CH₂C(O)OH,—CH₂SH, —CH₂S—SCH₂CH(NH₂)C(O)OH, —CH₂CH₂C(O)OH, —CH₂CH₂C(O)NH₂,—(CH₂)₄NH₂, —CH₂CH₂CH(OH)CH₂NH₂, —CH₂CH(CH₃)₂, —CH(CH₃)CH₂(CH₃),—CH₂CH₂SCH₃, —CH₂OH, —CH(OH)(CH₃),

or R³¹ and R³², together with the N to which R³¹ is attached and the Cto which R³¹ is attached, form a 5-membered ring which is unsubstitutedor independently substituted with a hydroxyl group;

-   -   R¹ is selected from the group consisting of alkyl,        R²¹-substituted alkyl, cycloalkyl, heterocycloalkyl,        cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —C≡CR³ and        —CR³═CR⁴R⁵,

wherein each of the alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R¹ is independentlyunsubstituted or substituted with one to five independently selected R²⁰moieties which can be the same or different, each R²⁰ moiety beingindependently selected from the group of R²⁰ moieties below,

each R², R⁴ and R⁵ is the same or different and each is independentlyselected from the group consisting of H, halo, alkyl, R²²-substitutedalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl,aryl, heteroaryl, —OR⁶, —C(O)R⁷, —C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵,—N(═C—O—NR²⁴R²⁵), —NR²⁴S(O)₂R²⁵,

wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R², R⁴ and R⁵ isindependently unsubstituted or substituted with one to fourindependently selected alkyl, R²²-substituted alkyl or R²² moietieswhich can be the same or different, each R²² moiety being independentlyselected from the group of R²² moieties below;

each R³ is the same or different and is independently selected from thegroup consisting of H, alkyl, R²²-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—OR⁶, —C(O)R⁷, —C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵) and—NR²⁴S(O)₂R²⁵,

each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R³ is independentlyunsubstituted or substituted with one to four independently selectedalkyl, R²²-substituted alkyl or R²² moieties which can be the same ordifferent, each R²² moiety being independently selected from the groupof R²² moieties below;

each R⁶ is independently selected from the group consisting of H, alkyland —CF₃;

each R⁷ is independently selected from the group consisting of H, alkyl,heteroaryl and —CF₃;

each R²⁰ is independently selected from the group consisting of: alkyl,R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³,—C(O)OR³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)R⁵, —CF₃, —OCF₃,—CF₂CF₃, —C(═NOH)R³, aryl, halo-substituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵,

wherein each of the aryl, halo-substituted aryl, heteroaryl, cycloalkyland heterocycloalkyl groups of R²⁰ is independently unsubstituted orsubstituted with one to four independently selected R²² moieties whichcan be the same or different, each R²² moiety being independentlyselected from the group of R²³ moieties below,

or two R²⁰ groups taken together with the carbon to which both R²⁰groups are attached is

R²¹ is one to three substituents independently selected from the groupconsisting of: —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³, —C(O)OR³,—C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —SO_(x)R⁵, —CF₃, —OCF₃, —CF₂CF₃,—C(═NOH)R³, R²³-substituted alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵;

wherein each of the aryl, halo-substituted aryl, heteroaryl, cycloalkyl,and heterocycloalkyl groups of R²¹ is independently unsubstituted orsubstituted with one to four independently selected R²³ moieties whichcan be the same or different, each R²³ moiety being independentlyselected from the group of R²³ moieties below,

or two R²¹ groups taken together with the carbon to which both R²¹groups are attached is

each R²² is independently selected from the group consisting of: halo,alkynyl, aryl, heteroaryl, —OR²⁴, —(C₁–C₆ alkyl)-OR²⁴, —CN, —NO₂,—NR²⁴R²⁵, —C(O)R²³, —C(O)OR²³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵,—S(O)_(x)R²³, —CF₃, —OCF₃, —CF₂CF₃, —C(═NOH)R²³, —N(R²⁴)S(O)_(x)R²⁵,—N(R²⁴)C(O)R²⁵, and —N(R²⁴)C(O)NR²⁴R²⁵,

or two R²² groups taken together with the carbon to which both R²²groups are attached is

each R²³ is independently selected from the group consisting of H,hydroxyl, halo and alkyl;

each R²⁴ is independently selected from the group consisting of H andalkyl;

each R²⁵ is independently selected from the group consisting of H,hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl, heteroaryl, —NR²⁴R²⁴,—(C₁ to C₆ alkyl)NR²⁴N²⁴, —CF₃ and —S(O)_(x)R²³;

each R²⁶ is independently selected from the group consisting of H,hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl, heteroaryl and —NR³R⁴;

R²⁷ is independently selected from the group consisting of heteroaryl,heterocycloalkyl and —NR²⁴R²⁵;

R³⁰ is independently selected from the group consisting of H and R²⁰substituent groups above;

R⁴⁰ is independently selected from the group consisting of H and R²⁰substituent groups above,

or R³⁰ and R⁴⁰, taken together with the carbon to which R³⁰ and R⁴⁰ areattached, is

with the proviso that at least one of V or T is selected from the groupconsisting of —C(O)N(R³)(OR⁴), —C(O)OR³ and —C(O)NR²⁴R²⁵, and

when —(W)_(n)-X-U— is alkylene, R¹ is not alkyl.

In another embodiment, a compound of Formula I is provided with theprovisos that at least one of V or T is selected from the groupconsisting of —C(O)N(R³)(OR⁴), —C(O)OR³ and —C(O)NR²⁴R²⁵, and

-   when —(W)_(n)-X-U— is alkylene, R¹ is not alkyl, and-   when —(W)_(n)-X- is alkylene, —Y— is not —N(R²⁴)C(O)—, and-   when one of T or V is —NR²⁵S(O)_(x)R³, the other of T or V is not    —C(O)NR²⁵OR³.

Another aspect of the present invention is a composition comprising atleast one of the above compounds. Methods of using the compounds for thetreatment of MMP and TNF-α mediated diseases and conditions also areprovided. The compounds of the invention may be used alone or incombination with other appropriate therapeutic agents.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified in all instances by the term “about.”

DETAILED DESCRIPTION OF THE INVENTION

In its several embodiments, the present invention provides a novel classof inhibitors of MMP and TNF-α convertase, pharmaceutical compositionscontaining one or more of the compounds, methods of preparingpharmaceutical formulations comprising one or more such compounds, andmethods of treatment, prevention or amelioration of one or more of thesymptoms of inflammation.

In one embodiment, the present invention provides compounds which arerepresented by structural Formula (I) above or a pharmaceuticallyacceptable salt, solvate or isomer thereof, wherein the various moietiesare as described above.

In one embodiment, m is 4. In another embodiment, m is 3. In anotherembodiment, m is 2. In another embodiment, m is 1.

In another embodiment, R³⁰ is H or —(C₁–C₆)alkyl. In another embodiment,R³⁰ is H.

In another embodiment, R⁴⁰ is H or —(C₁–C₆)alkyl. In another embodiment,R⁴⁰ is H.

In another embodiment, T is selected from the group consisting of—C(O)R⁴, —C(O)OR³, —C(O)NR²³R²⁵, and —C(O)NR²³OR³.

In one embodiment, T is —C(O)R⁴ in which R⁴ is a pyrrolidinyl ring thatis unsubstituted or substituted with one to three R²² moieties which areeach independently selected from the group consisting of —OR²⁴, —(C₁–C₆alkyl)-OR²⁴ and —NR²³R²⁴. Preferred R²² moieties are hydroxyl,hydroxyalkyl and alkylamino and amino.

In another embodiment, T is —C(O)OR³ in which R³ is alkyl.

In another embodiment, T is —C(O)NR²³R²⁵ in which R²³ is H or alkyl andR²⁵ is H, alkyl or —(C₁ to C₆ alkyl)NR²³N²⁴.

In another embodiment, T is —C(O)NR²³OR³ in which R²³ is H or alkyl andR³ is H or alkyl.

In another embodiment, V is —C(O)NR²³OR³ in which R²³ is H or alkyl andR³ is H or alkyl. In another embodiment, V is —C(O)OR³ in which R³ is Hor alkyl, such as methyl.

In another embodiment, W is —C(R³)(R⁴)— in which R³ is H and R⁴ is H orW is a covalent bond.

In another embodiment, n is 1.

In another embodiment, X is arylene which is unsubstituted orsubstituted with one to two independently selected R²⁰ moieties whichcan be the same or different.

In another embodiment, X is phenylene which is unsubstituted orsubstituted with one or two halo substituents which can be the same ordifferent.

In another embodiment, X is a heteroarylene which is unsubstituted orsubstituted with one to two independently selected R²⁰ moieties whichcan be the same or different.

In another embodiment, X is a heteroarylene selected from the groupconsisting of

which is unsubstituted or substituted with one or two halo substituents,such as Cl, F or I, which can be the same or different.

In another embodiment, U is —Y—(C(R³)(R⁴))_(q)—. In another embodiment,Y is —O—. In another embodiment, q is 1, R³ is H or alkyl and R⁴ is H oralkyl.

In another embodiment, R¹ is selected from the group consisting ofcycloalkyl, aryl and heteroaryl, wherein each of the cycloalkyl, aryland heteroaryl groups of R¹ is independently unsubstituted orsubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰ moieties above.

In another embodiment, R¹ is a cycloalkyl group selected from the groupconsisting of cyclopropyl, cyclobutyl and cyclohexyl, wherein each ofthe cycloalkyl groups is independently unsubstituted or substituted withone to five independently selected R²⁰ moieties which can be the same ordifferent, each R²⁰ moiety being independently selected from the groupof R²⁰ moieties above, such as alkyl.

In another embodiment, R¹ is an aryl group selected from the groupconsisting of phenyl, naphthyl, indanyl and tetrahydronaphthalenyl,wherein each of the aryl groups is independently unsubstituted orsubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰ moieties above, such as alkyl.

In another embodiment, R¹ is a heteroaryl group selected from the groupconsisting of chromanyl, quinolyl, isoquinolyl, triazolyl, pyridyl,imidazolyl, thiazolyl, benzodioxolyl and

wherein each of the heteroaryl groups is independently unsubstituted orsubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, each R²⁰ moiety being independentlyselected from the group of R²⁰ moieties, such as alkyl, R²¹-substitutedalkyl, halo, amino, carboxamide, aryl, heteroaryl, heterocycloalkyl and—OR³.

In another embodiment, R¹ is a fused bicyclic aryl group which isunsubstituted or substituted with one to three independently selectedR²⁰ moieties which can be the same or different.

In another embodiment, R¹ is a fused bicyclic heteroaryl group which isunsubstituted or substituted with one to three independently selectedR²⁰ moieties which can be the same or different.

In another embodiment, R² is H.

In another embodiment, each R³ is independently H, alkyl or aryl.

In another embodiment, each R⁴ is independently H, alkyl or aryl.

In another embodiment, each R⁵ is independently H, alkyl or aryl.

In another embodiment, each R²⁰ is independently selected from the groupconsisting of alkyl, R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂,—NR³R⁴, —C(O)OR³, —S(O)_(x)R⁵, —CF₃, —OCF₃, aryl, heteroaryl,cycloalkyl, wherein each of the aryl, heteroaryl and cycloalkyl groupsof R²⁰ is independently unsubstituted or substituted with one to fourindependently selected R²² moieties which can be the same or different,each R²² moiety being independently selected from the group of R²³moieties.

In another embodiment, R²⁰ is a heteroaryl group selected from the groupconsisting of pyrazinyl, pyrrolyl, pyridyl and morpholinyl.

In another embodiment, R²⁰ is a cycloalkyl selected from the groupconsisting of cyclopropyl, cyclobutyl and cyclohexyl.

In another embodiment, R²⁰ is a heterocycloalkyl selected from the groupconsisting of piperazinyl and pyrrolidinyl.

In another embodiment, each R²⁰ moiety is selected from the groupconsisting of —(C₁–C₆)alkyl and aryl.

In another embodiment, M is —(C(R³⁰)(R⁴⁰)_(m)—, wherein m is 1 to 4; Vis —C(O)OR³ or —C(O)NR²⁵OR³; T is R²¹-substituted alkyl, —CN, —C(O)OR³,—C(O)NR²⁵OR³, —C(O)NR²⁴R²⁵, —C(O)R⁴ or —C(R⁴)(═N(OR³)); W is a covalentbond or —(C(R³)(R⁴))_(n2); X is arylene or heteroarylene, each of whichcan be independently unsubstituted or substituted with one to fourindependently selected R²⁰ moieties; R¹ is cycloalkyl, aryl, heteroaryl,each of which can be independently unsubstituted or substituted with oneto four independently selected R²⁰ moieties; R² is H; and each of theother variables are as above in the Summary of the Invention.

A preferred group of compounds are shown in Table 1 below.

Except where stated otherwise, the following definitions applythroughout the present specification and claims. Additionally, alltechnical and scientific terms used herein have the same meaning as iscommonly understood by one skilled in the art to which this inventionbelongs. These definitions apply regardless of whether a term is used byitself or in combination with other terms. Hence the definition of“alkyl” applies to “alkyl” as well as to the “alkyl” portions of“alkoxy”, etc.

“Patient” or “subject” includes both humans and animals.

“Mammal” includes humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group that may be straight orbranched and comprising 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain 1 to about 12 carbon atoms in the chain.More preferred alkyl groups contain 1 to about 6 carbon atoms in thechain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl, are attached to a linear alkyl chain. “Loweralkyl” means a group having about 1 to about 6 carbon atoms in the chainwhich may be straight or branched. The alkyl may be substituted.

The phrase “R²¹-substituted alkyl” means that the alkyl group can besubstituted by one or more R²¹ substituents that may be the same ordifferent, each substituent being independently selected from the groupconsisting of R²¹ substituents listed above. Each of the aryl,halo-substituted aryl, heteroaryl, cycloalkyl and heterocycloalkylgroups of R²¹ can be unsubstituted or independently substituted with oneto four independently selected R²³ moieties which can be the same ordifferent, each R²³ moiety being independently selected from the groupof R²³ moieties above.

The phrase “R²²-substituted alkyl” means that the alkyl group can besubstituted by one or more R²² substituents that maybe the same ordifferent, each substituent being independently selected from the groupconsisting of R²² substituents listed above.

The phrase “R⁵²-substituted alkyl” means that the alkyl group can besubstituted by one or more R⁵² substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of R²¹ substituents listed above.

“Alkenyl” means an aliphatic hydrocarbon group comprising at least onecarbon-carbon double bond and which may be straight or branched andcomprising 2 to about 15 carbon atoms in the chain. Preferred alkenylgroups have 2 to about 12 carbon atoms in the chain; and more preferably2 to about 6 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl, are attached to alinear alkenyl chain. “Lower alkenyl” means 2 to about 6 carbon atoms inthe chain which may be straight or branched. The alkenyl may besubstituted and the term “R³⁵-substituted alkenyl” means that thealkenyl group may be substituted by one or more substituents which canbe the same or different, each substituent being independently selectedfrom the group consisting of R³⁵ substituents listed above.

“Aryl” means an aromatic monocyclic or multicyclic (for example,bicyclic) ring system comprising about 5 to about 14 carbon atoms,preferably about 6 to about 10 carbon atoms. The aryl groups of T, V, X(arylene) and R¹ can be unsubstituted or independently substituted withone to five independently selected R²⁰ moieties which can be the same ordifferent, and are as defined herein. The aryl groups of R², R³, R⁴, R⁵and R²⁰ can be unsubstituted or independently substituted with one tofour independently selected R²² moieties which can be the same ordifferent, and are as defined herein. The aryl groups of R²¹ can beunsubstituted or independently substituted with one to fourindependently selected R²³ moieties which can be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl.

“Alkylene” refers to an alkanediyl group commonly having free valencieson two carbon atoms. Non-limiting examples include methylene, propyleneand the like.

“Arylene” is a bivalent group derived from an aromatic hydrocarbon byremoval of a hydrogen atom from two ring carbon atoms. Non-limitingexamples include phenylene and the like.

“Heteroarylene” is a bivalent group derived from a heterocyclic aromaticcompound by removal of a hydrogen atom from two ring atoms such as, forexample, the bivalent group derived from pyridine, pyrrole and the like.The bonds to the parent moiety can be through different carbon ringatoms, different hetero ring atoms or through a carbon ring atom and ahetero ring atom.

“Heteroaryl” represents cyclic aromatic groups of 5 or 6 atoms orbicyclic groups of 8 to 12 atoms having 1, 2 or 3 heteroatomsindependently selected from O, S or N, said heteroatom(s) interrupting acarbocyclic ring structure and having a sufficient number of delocalizedpi electrons to provide aromatic character, provided that the rings donot contain adjacent oxygen and/or sulfur atoms. Preferred monocyclicheteroaryls contain about 5 to about 6 ring atoms. Preferred bicyclicheteroaryls contain about 10 ring atoms. The heteroaryl groups of T, V,X (heteroarylene) and R¹ can be unsubstituted or independentlysubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, and are as defined herein. The heteroarylgroups of R², R³, R⁴, R⁵ and R²⁰ can be unsubstituted or independentlysubstituted with one to four independently selected R²² moieties whichcan be the same or different, and are as defined herein. The heteroarylgroups of R²¹ can be unsubstituted or independently substituted with oneto four independently selected R²³ moieties which can be the same ordifferent, and are as defined herein. The prefix aza, oxa or thia beforethe heteroaryl root name means that at least a nitrogen, oxygen orsulfur atom respectively, is present as a ring atom. Nitrogen atoms canform an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl,3-pyridyl and 4-pyridyl. Useful 6-membered heteroaryl groups includepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, morpholinyl and the likeand the N-oxides thereof. Useful 5-membered heteroaryl rings includefuryl, triazolyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, isoxazolyl and the like. Typical bicyclic groupsare benzo-fused ring systems derived from the heteroaryl groups namedabove, e.g. quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,benzofuranyl, benzothienyl, benzodioxolyl, indolyl and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl groups of T, V, X (cycloalkylene) and R¹ canbe unsubstituted or independently substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,and are as defined herein. The cycloalkyl groups of R², R³, R⁴, R⁵ andR²⁰ can be unsubstituted or independently substituted with one to fourindependently selected R²² moieties which can be the same or different,and are as defined herein. The cycloalkyl groups of R²¹ can beunsubstituted or independently substituted with one to fourindependently selected R²³ moieties which can be the same or different,and are as defined herein. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl groups of T, V and R¹ can be unsubstituted or independentlysubstituted with one to five independently selected R²⁰ moieties whichcan be the same or different, and are as defined herein. Thecycloalkenyl groups of R², R³, R⁴, R⁵ and R²⁰ can be unsubstituted orindependently substituted with one to four independently selected R²²moieties which can be the same or different, and are as defined herein.The cycloalkenyl groups of R²¹ can be unsubstituted or independentlysubstituted with one to four independently selected R²³ moieties whichcan be the same or different, and are as defined herein. Non-limitingexamples of suitable monocyclic cycloalkenyls include cyclopentenyl,cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of asuitable multicyclic cycloalkenyl is norbornyl.

“Heterocycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocycloalkenyl rings contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before the heterocyclenyl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The heterocycloalkenyl groups of T, V and R¹ canbe unsubstituted or independently substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,and are as defined herein. The heterocycloalkenyl groups of R², R³, R⁴,R⁵ and R²⁰ can be unsubstituted or independently substituted with one tofour independently selected R²² moieties which can be the same ordifferent, and are as defined herein. The heterocycloalkenyl groups ofR²¹ can be unsubstituted or independently substituted with one to fourindependently selected R²³ moieties which can be the same or different,and are as defined herein. The nitrogen or sulfur atom of theheterocycloalkenyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic aza heterocycloalkenyl groups include1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 2-imidazolinyl,2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocycloalkenyl groups include 3,4-dihydro-2H-pyranyl,dihydrofuranyl, and the like. Non-limiting example of a suitablemulticyclic oxa heterocycloalkenyl group is 7-oxabicyclo[2,2,1]heptenyl.Non-limiting examples of suitable monocyclic thia heterocycloalkenylrings include dihydrothiophenyl, dihydrothiopyranyl, and the like.

“Heterocycloalkyl” means a non-aromatic saturated monocyclic ormulticyclic ring system comprising about 3 to about 10 ring atoms,preferably about 5 to about 10 ring atoms, in which one or more of theatoms in the ring system is an element other than carbon, for examplenitrogen, oxygen or sulfur, alone or in combination. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocycloalkyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocycloalkyl groups of T, V, X (cycloalkylene) and R¹can be unsubstituted or independently substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,and are as defined herein. The heterocycloalkyl groups of R², R³, R⁴, R⁵and R²⁰ can be unsubstituted or independently substituted with one tofour independently selected R²² moieties which can be the same ordifferent, and are as defined herein. The heterocycloalkyl groups of R²¹can be unsubstituted or independently substituted with one to fourindependently selected R²³ moieties which can be the same or different,and are as defined herein. The nitrogen or sulfur atom of theheterocycloalkyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, 1,3-dioxolanyl, tetrahydrofuranyl,tetrahydrothiophenyl and the like.

“Heterocycloalkylene” is a bivalent group derived from a heterocycliccycloalkyl compound by removal of a hydrogen atom from two ring atomssuch as, for example, the bivalent group derived from piperazine and thelike. The bonds to the parent moiety can be through different carbonring atoms, different hetero ring atoms or through a carbon ring atomand a hetero ring atom.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl group is aspreviously defined. Preferred hydroxyalkyls contain lower alkyl.Non-limiting examples of suitable hydroxyalkyl groups includehydroxymethyl and 2-hydroxyethyl.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

As a general note, any open-ended nitrogen atom with unfulfilled valencein the chemical structures in this application refers to NH, or in thecase of a terminal nitrogen, —NH₂. Similarly, any open-ended oxygen atomwith unfulfilled valence in the chemical structures in this applicationrefers to —OH and any open-ended carbon atom with unfilled valence isappropriately filled with —H.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound of the present invention effective ininhibiting TNF-α or MMP and thus producing the desired therapeutic,ameliorative, inhibitory or preventative effect.

The compounds of formula I can form salts which are also within thescope of this invention. Reference to a compound of formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the formula I may be formed, for example, by reacting a compound offormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulforiates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates,sulfonates (such as those mentioned herein), tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) undecanoates, and the like.Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by S. Berge et al, Journal ofPharmaceutical Sciences (1977) 66(1)1–19; P. Gould, International J. ofPharmaceutics (1986) 33 201–217; and Anderson et al, The Practice ofMedicinal Chemistry (1996), Academic Press, New York). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as benzathines, dicyclohexylamines, hydrabamines(formed with N,N-bis(dehydroabietyl)ethylenediamine),N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromidesand iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, anddiamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyland phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of formula I, and salts, solvates and prodrugs thereof, mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

When a variable appears more than once in the structural formula, forexample R³ or R⁵, the identity of each variable appearing more than oncemay be independently selected from the definition for that variable.

The compounds of the present invention can have pharmacologicalproperties, for example the compounds of Formula I can be inhibitors ofTACE (TNF-α) and/or MMP activity. The compounds of Formula I can haveanti-inflammatory activity and/or immunomodulatory activity and can beuseful in the treatment of diseases including but not limited to septicshock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusioninjury, malaria, mycobacterial infection, meningitis, psoriasis,congestive heart failure, fibrotic diseases, cachexia, graft rejection,cancers such as cutaneous T-cell lymphoma, diseases involvingangiogenesis, autoimmune diseases, skin inflammatory diseases,inflammatory bowel diseases such as Crohn's disease and colitis, osteoand rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,adult Still's disease, ureitis, Wegener's granulomatosis, Behcehedisease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis,multiple sclerosis, radiation damage, hyperoxic alveolar injury,periodontal disease, HIV, non-insulin dependent diabetes mellitus,systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathicpulmonary fibrosis, bronchopulmonary dysplasia, retinal disease,scleroderma, osteoporosis, renal ischemia, myocardial infarction,cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis,transplant rejection, atopic dermatitis, vasculitis, allergy, seasonalallergic rhinitis, reversible airway obstruction, adult respiratorydistress syndrome, asthma, chronic obstructive pulmonary disease (COPD)and/or bronchitis. It is contemplated that a compound of this inventionmay be useful in treating one or more of the diseases listed.

Additionally, a compound of the present invention may be co-administeredor used in combination with disease-modifying antirheumatic drugs(DMARDS) such as methotrexate, azathioprine, leflunomide,pencillinamine, gold salts, mycophenolate mofetil, cyclophosphamide andother similar drugs. They may also be co-administered with or used incombination with NSAIDS such as piroxicam, naproxen, indomethacin,ibuprofen and the like; COX-2 selective inhibitors such as Vioxx® andCelebrex®; immunosuppressives such as steroids, cyclosporin, Tacrolimus,rapamycin and the like; biological response modifiers (BRMs) such asEnbrel®, Remicade®, IL-1 antagonists, anti-CD40, anti-CD28, IL-10,anti-adhesion molecules and the like; and other anti-inflammatory agentssuch as p38 kinase inhibitors, PDE4 inhibitors, other chemicallydifferent TACE inhibitors, chemokine receptor antagonists, Thalidomide:and other small molecule inhibitors of pro-inflammatory cytokineproduction.

Also, a compound of the present invention may be co-administered or usedin combination with an Hi antagonist for the treatment of seasonalallergic rhinitis and/or asthma. Suitable H1 antagonists may be, forexample, Claritin®, Clarinex®, Allegra®, or Zyrtec®.

In another aspect, the invention provides a method for treatingrheumatoid arthritis comprising administering a compound of the formulaI in combination with compound selected from the class consisting of aCOX-2 inhibitor e.g. Celebrex® or Vioxx®; a COX-1 inhibitor e.g.Feldene®; an immunosuppressive e.g. methotrexate or cyclosporin; asteroid e.g. β-methasone; and anti-TNF-α compound, e.g. Enbrel® orRemicade®; a PDE IV inhibitor, or other classes of compounds indicatedfor the treatment of rheumatoid arthritis.

In another aspect, the invention provides a method for treating multiplesclerosis comprising administering a compound of the formula I incombination with a compound selected from the group consisting ofAvonex®, Betaseron, Copaxone or other compounds indicated for thetreatment of multiple sclerosis.

TACE activity is determined by a kinetic assay measuring the rate ofincrease in fluorescent intensity generated by TACE catalyzed cleavageof an internally quenched peptide substrate (SPDL-3). The purifiedcatalytic domain of recombinant human TACE (rhTACEc, Residue 215 to 477with two mutation (S266A and N452Q) and a 6×His tail) is used in theassay. It is purified from the baculovirus/Hi5 cells expression systemusing affinity chromatography. The substrate SPDL-3 is an internallyquenched peptide(MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with itssequence derived from the pro-TNFα cleavage site. MCA is(7-Methoxycoumarin-4-yl)acetyl. Dpa isN-3-(2,4-Dinitrophenyl)-L-2,3-diaminopropionyl.

A 50 μl assay mixture contains 20 mM HEPES, pH 7.3, 5 mM CaCl₂, 100 μMZnCl₂, 2% DMSO, 0.04% Methylcellulose, 30 μM SPDL-3, 70 pM rhTACEc and atest compound. RhTACEc is pre-incubated with the testing compound for 90min. at 25° C. Reaction is started by addition of the substrate. Thefluorescent intensity (excitation at 320 nm, emission at 405 nm) wasmeasured every 45 seconds for 30 min. using a fluorospectrometer (GEMINIXS, Molecular Devices). Rate of enzymatic reaction is shown as Units persecond. Effect of a test compound is shown as % of TACE activity in theabsence of the compound.

Useful compounds for TACE inhibitory activity can exhibit K_(i) valuesof less than about 1000 nm, preferably about 0.01 nm to about 1000 nm,more preferably about 0.1 nm to about 100 nm, more preferably about 0.1to about 15 nm, and most preferably less that about 15 nm.Representative compounds of the invention which exhibit excellent TACEinhibitory activity (K_(i) values of less than about 20 nanomolar, nm)are as follows: Compounds BX, JH, BD, BW, KM, BL, O, P, JY, JX, CV, CA,JG, BV, CC, JO, CP, JN, CT, FQ, DE, FN, KX, LB, IZ, GV, JB, JA, LA, KY,BY, JD, BO, BP, DA, FG, CU, CW, LC, JF, DB, CS, JC, JE, KZ, CO, JT, JU,JS, JR, FY, CR, GA, GB, CY, JV, BR, CZ, FZ, BQ, CQ, FX, FU, FW, JW, FV,CN, CA, JP, BS, LM, LI and LH. The Compound letter designations refer tothe letter designations for the various structures in Table 1 in theEXAMPLES section found below.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipients that are suitable forthe manufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets forcontrolled release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredients is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules where in the active ingredient is mixed with water oran oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example, polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample, ethyl or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, e.g., sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil,e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffinor mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, e.g., soy beans, lecithin, and estersor partial esters derived from fatty acids and hexitol anhydrides, forexample, sorbitan monooleate, and condensation products of the saidpartial esters with ethylene oxide, e.g., polyoxyethylene sorbitanmonooleate. The emulsions may also contain sweetening and flavoringagents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, e.g., as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that maybe employed are water, Ringer's solutionand isotonic sodium chloride. solution. In addition, sterile fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. The compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of The invention are employed. (Forpurposes of this application, topical application shall includemouthwashes and gargles.)

The compounds for the present invention can be administered in theintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen. Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, weight, sex and medical condition of the patient; the severityof the condition to be treated; the route of administration; the renaland hepatic function of the patient; and the particular compound thereofemployed. A physician or veterinarian of ordinary skill can readilydetermine and prescribe the effective amount of the drug required toprevent, counter, arrest or reverse the progress of the condition.Optimal precision in achieving concentration of drug within the rangethat yields efficacy without toxicity requires a regimen based on thekinetics of the drug's availability to target sites. This involves aconsideration of the distribution, equilibrium, and elimination of adrug. Preferably, doses of the compound of Formula I useful in themethod of the present invention range from 0.01 to 1000 mg per day. Mostpreferably, dosages range from 0.1 to 500 mg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01 to 1000 milligrams of the active ingredient,particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0,50.0, 100 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Aneffective amount of the drug is ordinarily supplied at a dosage level offrom about 0.0002 mg/kg to about 50 mg/kg of body weight per day. Therange is more particularly from about 0.001 mg/kg to 1 mg/kg of bodyweight per day.

Advantageously, the active agent of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in dividend doses of two, three or four time daily.

The amount of active ingredient that may be combined with the carriermaterials to produce single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route or administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The compounds of the invention may be produced by processes known tothose skilled in the art and as shown in the following reaction schemesand in the preparations and examples described below.

EXAMPLES

The following abbreviations are used in the procedures and schemes:dichloromethane (DCM); tetrabutylammonium bromide (TBAB); Benzyl (Bn);acetonitrile (MeCN); ethyl acetate(EtOAc); Tetrahydrofuran (THF);Trifluoroacetic acid (TFA); 1-hydroxy-7-aza-benzotriazole (HOAt);1-hydroxylbenzotriazole(HOAt); N-methylmorpholine (NMM);1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl);diisopropylethyl amine (DIEA); 1-hydroxybenzotriazole (HOBt);Dimethoxyethane (DME).[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)](Selectfluor); 4-N,N-dimethylaminopyridine(DMAP); 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU);

Saturated (sat.); anhydrous. (anhyd); room temperature (rt); hour (h);Minutes (Min), Retention Time (R_(t)); molecular weight (MW); milliliter(mL); gram (g). milligram (mg); equivalent (eq).

All NMR data were collected on 400 MHz NMR spectrometers unlessotherwise indicated. LC-Electrospray-Mass spectroscopy with a C-18column and 5% to 95% MeCN in water as the mobile phase was used todetermine the molecular mass and retention time.

The compounds in the invention may be produced by processes known tothose skilled in the art and as shown in the following reaction schemesand in the preparations and examples described below. Table 1 containsthe compounds with retention time/observed MW and/or NMR data. Thecompounds of Table 1 can be obtained using synthetic methods similar tothose below as listed in the last column of Table 1 using appropriatereagents known to those skilled in the art.

Synthesis of Compound 2

To a solution of 50 g (0.28 mol) of compound 1 in 500 mL of anhyd. DCMin an ice bath was added 560 mL 1 N BBr₃ in DCM. The final solution wasstirred for 30 min before it was quenched with 200 mL MeOH. After thesolvent was evaporated, the residue was dissolved in 500 mL of DCM,washed with water, sat. NaHCO₃, and brine. The organic phase was driedover anhyd. sodium sulfate. The solvent was evaporated to give 41.5 g ofdesired compound 2 (90%) which was used in the next step withoutpurification.

Synthesis of Compound 3

To a mixture of 41.5 g of Compound 2 in 500 mL DCM, was added 10 eq.anhyd. K₂CO₃, 0.05 eq of tetrabutylammonium bromide (TBAB), and 1 eq. ofbenzylbromide. The mixture was stirred overnight, and the solid wasfiltered and washed with DCM. The combined organic solution was washedwith water, saturated aqueous Na₂CO₃, brine, and dried over anhyd.sodium sulfate. The solvent was evaporated to give 57.6 g of compound 3(90%), which was used in the next steps without purification.

Synthesis of Compound 4

To a solution of 57.6 g of Compound 3 in 500 mL of hexane was addedK₂CO₃ (10 eq), TBAB (0.05 eq) and paraformaldehyde (20 eq), and thefinal mixture was refluxed overnight under effective stirring. Thereaction mixture was partitioned between water and DCM, and the aqueouslayer was extracted with DCM. The combined organic solution was washedwith water, sat. Na₂CO₃, brine, and dried over anhyd. Na₂SO₄. Thesolvent was removed and the residue chromatographed with 1–10%ethylacetate in hexane to give 31 g of compound 4 (51%).

Synthesis of Compound 5

To a solution of 31 g of Compound 4 in 500 mL of MeCN was addedS-carbo-tert-butoxymethyl-tetrahydrothiophene bromide (1.1 eq) and DBU(1.5 eq). The solution was stirred overnight and the solvent wasevaporated. The residue dissolved in 500 mL DCM. The organic solutionwas washed with H₂O, 0.1 N HCl, water, brine, and dried over anhyd.Na₂SO₄. After removal of the solvent, the residue was chromatographedwith 1–20% EtOAc/Hexane to give 32 g of compound 5 (73%).

Synthesis of 6

A mixture of 100 mL methanol solution of 2.0 g of Compound 5 with 200 mgof 10% Pd/C was stirred under H₂ until the starting materialdisappeared. The solution was filtered and the solvent evaporated togive compound 6 in quantitative yield.

Chiral Resolution of Compound 6

Compound 6 (1.0 g) was resolved with an OD chiral column eluted with 5%IPA/Hexane (120 mL/min). The first peak at 19.9 min was collected asenantiomer 6a and the second peak at 28.17 min was collected asenantiomer 6b.

Synthesis of Compound 7

To a mixture of compound 6 (99 mg, 0.34 mmol), 31 mg of TBAB, 154 mg ofanhyd K₂CO₃ in 2 mL of anhyd DCM was added 0.06 mL of benzyl bromide.The final solution was heated to 40° C. for 3 h. The mixture was dilutedwith 50 mL DCM and washed with water before the organic layer was driedover anhyd Na₂SO₄. The solvent was evaporated to give compound 7, whichwas used in the next step without purification.

Synthesis of Compound 8

A solution of Compound 7 (100 mg) in 30% TFA in DCM was kept for 4 hbefore the solvent was evaporated. The residue was adjusted to pH˜9.5with a 1:1 ratio of sat. NaHCO₃/Na₂CO₃ and the aqueous solution washedwith ether. After acidification to pH˜2, the aq layer was extracted withEtOAc. The combined organic layers were dried and solvent removed togive compound 8, which was used without purification for next step.

Synthesis of Compound 9

To a DCM solution of compound 8 at 0° C. were added HOAt (47 mg),O-tritylhydroxylamine (284 mg) and NMM 0.23 mL followed by 105 mg EDCl.The final solution was stirred overnight and the reaction mixture wasdiluted with 50 mL DCM and washed with NaHCO₃ and water. The organiclayer was dried over anhyd Na₂SO₄. After removal of solvent the residuewas chromatographed on a silica gel column eluting with 10–40% EtOAc inhexane to give 132 mg of Compound 9.

Synthesis of Compound 10

To a 2 mL solution of 60 mg of Compound 9 was added 55 mg oftriethylsilane followed by 230 mg of TFA. The solution was evaporatedand the residue was purified through a C-18 reverse phase HPLC columneluting with 5–95% of acetonitrile in water to give 32 mg of Compound 20as a white solid.

¹H NMR (CD₃CN) of 10: δ 7.6–7.4 (m, 5H); 7.3 (m, 1H); 6.95 (m, 3H); 5.2(m, 2H); 3.7 (s, 3H); 2.6 (m, 1H); 2.05 (m, 1H); 1.85 (m, 1H).

Synthesis of Compound 11

A solution 150 mg of Compound 9 and 1 g of LiOH.H₂O in a mixture of 20mL MeOH, 10 mL THF and 10 mL H₂O was refluxed for 30 min. The solventwas evaporated and the residue was dissolved in a mixture of 100 mLDCM/100 mL of sat. aq ammonium chloride. The organic layer wasseparated, dried over anhyd sodium sulfate, and the solvent evaporatedto give 150 mg of 11.

Synthesis of Compound 11a

Compound 11 was dissolved in 2 ml of DMF followed by addition of 6 eq.of ammonium chloride, 2.5 eq. of HOBt, 25 eq of DIEA and 2.5 eq of EDCl.The mixture was stirred overnight followed by dilution with DCM andwashed with water. The organic layer was dried over anhyd. sodiumsulfate and the solvent was evaporated. The residue was chromatographedwith a silica gel column to give 106 mg of Compound 11a.

Synthesis of Compound 12

Compound 12 was synthesized from 11a following a procedure similar tothe transformation from 9 to 10 (Method 2).

¹H NMR(CDCl₃) of 12: δ 7.4–7.6 (m, 5H); 7.29 (m, 1H); 7.05 (m, 3H); 6.4(br. s, 1H); 5.85 (br. s, 1H); 5.2 (m, 2H); 2.59 (m, 1H); 1.9 (m, 1H);1.75 (m, 1H).

Synthesis of Compound 14

Compound 14 was synthesized from 13 following procedures similar to thetransformation from 3 to 6 (Method 1).

Synthesis of Compound 15

Compound 15 was synthesized from 14 following procedures similar to thetransformation from 6 to 10 (Method 2).

¹H NMR(CD₃CN) of 15: δ 7.45–7.62 (m, 5H); 7.3 (m, 2H); 7.01 (m, 2H); 5.2(s, 2H); 4.18 (m, 2H); 2.6 (m, 1H); 2.02 (m, 1H); 1.85 (m, 1H); 1.23 (m,3H).

Synthesis of Compound 17

To a solution of 10.5 g of Compound 16 (40 mmol) in 100 mL of anhyd THFat −78° C. was added 53 mL of 1.5 M tert-Butyllithium in hexane over 5min. After the solution was stirred at −78° C. for 1 h, it was addedinto a mixture of CuCN (40 mmol) in 20 mL of THF at 0° C. The solutionwas stirred for 30 min before it was cooled to −78° C. and added to asolution of methyl 2-(bromomethyl)acrylate (29 mmol) in 20 mL of THF at−78° C. The reaction was stirred for 30 min at −78° C. followed bywarming to −10° C. for 10 min before it was poured into a mixture ofsaturated NH₄Cl in ice. The mixture was extracted with DCM and theresidue chromatographed with 10% EtOAc/Hexane to give 6.0 g of thedesired product 17.

¹H NMR (CDCl₃) of 17: δ 7.5–7.3 (m, 5H); 7.13 (d, 2H); 6.94 (d, 2H);6.22 (br s, 1H); 5.47 (br s, 1H); 5.05 (s, 2H); 3.75 (s, 3H); 3.59 (s,2H).

Synthesis of Compound 18

Compound 18 was synthesized from 17 following a procedure similar to thetransformation from 4 to 5 (Method 1).

Synthesis of Compound 19

Compound 19 was synthesized from 18 following a procedure similar to thetransformation from 5 to 6 (Method 1).

Chiral Resolution of 19

Methods similar to the resolution of Compound 6 were used for theresolution of Compound 19. The first enantiomer was collected as 19a andthe second enantiomer collected as 19b.

Synthesis of Compound 19c

Compound 19c was synthesized from 19a following a procedure similar tothe transformation from 7 to 8 (Method 2).

Synthesis of Compound 20

Compound 20 was synthesized from 18 following a procedure similar to thetransformation of 7 to 8 (Method 2).

Synthesis of Compound 21

A solution of acid 20 (0.190 mg, 0.56 mmol), Wang hydroxylamine resin(0.500 g, 1 mmol/g), EDCl (0.172 g, 0.90 mmol), NMM (0.400 mL, 3.64mmol), and HOAt (0.075 g, 0.55 mmol) in DCM (7 mL) was agitated for 14hours at room temperature. The liquid was drained, and the resin waswashed with CH₂Cl₂ (3×), THF(3×), and MeOH(3×) in an alternatingsequence. The resin was dried under high vacuum to yield resin 21 (0.630g, 0.79 mmol/g).

Synthesis of Compound 22

A mixture of resin 21 (0.067 g, 0.79 mmol/g) and 1M Bu₄NOH in THF (2 mL)was agitated at 60° C. for 4 h. The liquid was drained and the resin waswashed with 1% AcOH in DMF (2×30 min.) followed by an alternating cycleof washes with MeOH (3×), THF (3×) and CH₂Cl₂ (3×). The resulting resinwas dried under high vacuum for 4 hours.

A mixture of the carboxylic acid resin prepared above (0.067 g, 0.79mmol/g), EDCl (0.045 g, 0.23 mmol), HOBt (0.030 g, 0.20 mmol) and NMM(0.026 mL, 0.24 mmol) in NMP (2 mL) was agitated for 20 minutes beforethe addition of benzyl amine (0.026 mL, 0.24 mmol). This mixture wasagitated for 18 hours at rt. The liquid was drained, and the resin waswashed with an alternating cycle of CH₂Cl₂ (3×), THF (3×), and MeOH(3×). The remaining resin was treated with 50% TFA/CH₂Cl₂ (2 mL) andagitated for 1 hour. The liquid was drained, and the remaining resin waswashed with CH₂Cl₂ (2×). Concentration of the liquid afforded Compound22 (10 mg, 0.023 mmol).

¹H NMR (CD₃CN/D₂O, 2:1) of 22: δ 7.29–7.44 (m, 6H), 7.14–7.07 (m, 4H),6.84–6.81 (m, 4H), 5.03 (s, 2H), 4.22–4.13 (m, 2H), 3.12–2.93 (m, 2H),2.07–2.03 (m, 1H), 1.49–1.46 (m, 1H), 1.40–1.38 (m, 1H).

Synthesis of Compound 23

To a solution of compound 19a (0.04 g) and4-chloromethyl-2-methylquinoline (1.5 eq) in 1 mL of DMF was added 0.25g of potassium carbonate and 20 mg of tetrabutylammonium iodide. Themixture was stirred overnight before it was partitioned in a mixture ofDCM/water. The aqueous layer was extracted twice with DCM and thecombined organic layer was dried and solvent removed. The residue waschromatographed to give compound 23 (0.08 g).

Synthesis of Compound 24

Compound 24 was synthesized from 23 following a procedure similar to thetransformation of 7 to 8 (Method 2).

Synthesis of Compound 25

Compound 25 was synthesized from 24 following a procedure similar to thetransformation of 8 to 9 (Method 2).

Synthesis of Compound 26

Compound 26 was synthesized from 25 following a procedure similar to thetransformation of 9 to 10 (Method 2).

¹H NMR (CD₃CN/D₂O, 2:1) of 26: δ 8.38 (m, 1H), 8.28 (m, 1H), 8.05 (m,1H). 8.01 (s, 1H); 7.88 (m, 1H); 7.20 (m, 2H); 7.04 (m, 2H); 5.71 (s,2H), 3.57 (s, 3H), 2.96–3.4 (m, 2H), 2.95 (s, 3H); 2.23 (m, 1H),1.49–1.46 (m, 2H).

Synthesis of Compound 25a

Compound 25a was synthesized from 25 using a procedure similar to thetransformation of 9 to 11 (Method 3).

Synthesis of Compound 27a

To a solution of acid 25a (0.043 g, 0.067 mmol) in CH₂Cl₂ (1 mL) at roomtemperature was added DMAP (0.025 mg, 0.20 mmol) and EDCl (0.033 g, 0.17mmol). This mixture was stirred for 25 minutes and 2-propanol (0.20 mL,2.6 mmol) was then added. The resulting mixture was stirred for 16hours. The reaction was quenched with H₂O and diluted with ethylacetate. The organic phase was removed, and the aqueous layer wasextracted with ethyl acetate (3×). The combined organic layers werewashed with H₂O (2×), brine (1×), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash chromatography to affordcompound 27a.

¹H NMR (CD₃OD): δ 8.4 (m, 1H), 8.05–8.02 (m, 3H), 7.93 (m, 1H), 7.25 (m,2H); 7.05 (m, 2H); 5.8 (s, 2H), 4.88 (m, 1H); 3.0–3.24 (m, 2H), 2.96 (s,3H); 2.24 (m, 1H); 1.5 (m, 2H); 1.1 (m, 6H).

Synthesis of Compound 27b

Compound 27b was synthesized from 25a following procedures similar tothe transformation of 11 to 12 (Method 3).

¹H NMR (CD₃OD) of 27b: δ 8.12 (m, 1H), 8.01 (m, 1H), 7.80 (m, 1H), 7.62(m, 2H); 7.23 (m, 2H); 7.01 (m, 2H); 5.57 (s, 2H), 3.1–3.3 (m, 2H); 2.74(s, 3H); 2.14 (m, 1H), 1.54 (m, 1H); 1.46 (m, 1H).

Synthesis of 28

Compound 28 was synthesized from 16 following procedures similar to thetransformation of 16 to 19 (Method 5).

Synthesis of 29

Compound 28 was synthesized following a procedure similar to thetransformation of 7 to 8 (Method 2).

Chiral Resolution of 29

Compound 29 was resolved with a Chiralpak AS column eluting with 40%iPrOH/hexanes (0.1% AcOH) at 70 mL/min. The first peak at was collectedas enantiomer 29a and the second peak was collected as enantiomer 29b.

Synthesis of Compound 30

To a methanolic solution of 29a (0.5 g) was added 6 drops of sulfuricacid and the solution was refluxed for 1 h. After removal of methanol,the residue was partitioned in a mixture of DCM/water. The water layerwas extracted with DCM (3×) and the combined organic layer was dried andsolvent evaporated to give 0.51 g of product 30.

Synthesis of Compound 31

Compound 31 was synthesized from 30 following a procedure similar to thetransformation of 6 to 7 (Method 2) or 19a to 23 (Method 7).

Synthesis of Compound 32

To a solution of Compound 31 (0.08 g) in 4 mL of methanol was added 100mg LiOH in 1 mL of water. The suspension was stirred for 2h at rt andthe solution was partitioned in a mixture of DCM/saturated ammoniumchloride. The aqueous layer was extracted with DCM and the combinedorganic layer was dried and solvent removed to give 75 mg of crude 32which was used for next step without purification.

Synthesis of Compound 33

Compound 33 was synthesized from 32 following procedures similar to thetransformation from 8 to 10 (Method 2).

¹H NMR (CD₃CN/D₂O, 2:1): δ 8.07–8.18 (m, 5H), 7.8 (m, 1H), 7.60 (m, 1H),7.5 (m, 3H); 7.23 (m, 2H); 7.01 (m, 2H); 5.57 (m, 2H), 3.97 (m, 2H);2.9–3.2 (m, 2H); 2.2 (m, 1H); 1.5 (m, 2H); 1.1 (m, 3H).

Synthesis of Compound 34

Compound 34 was synthesized from 32 following a procedure similar to thetransformation from 8 to 9 (Method 2) and then 9 to 12 (Method 3).

¹H NMR (CD₃OD) of 34: δ 8.3–8.5 (m, 3H), 8.05–8.15 (m, 3H), 7.85–7.97(m, 1H), 7.62–7.76 (m, 3H); 7.26 (m, 2H); 7.10 (m, 2H); 5.8 (s, 2H),3.1–3.3 (m, 2H); 2.14 (m, 1H), 1.54 (m, 1H); 1.46 (m, 1H).

Synthesis of Compound 37

A solution of 11.5 g of 35 (7.4 mmol), 36 (1 eq) andDiisopropylethylamine (1.5 eq) in 200 mL Acetonitrile was refluxed for 3h. After removing all the solvent, the solid (37, 22 g) was used fornext step without purification.

Synthesis of Compound 38

A solution of compound 37, (22 g) and 300 mL of 20% hydrazinemonohydrate in methanol was refluxed for 20 minutes. After removal ofthe solvents, the solid was partitioned between 1N NaOH and DCM. The aqlayer was extracted with DCM (×3) before the combined organic layerswere dried and evaporated to give 9.5 g crude product. The hydroxylaminewas mixed with 9.0 g of 2,4-dimethoxybenzaldehyde, 10 g of sodiumacetate in 200 mL of acetic acid. After the mixture was refluxed for 2h, white precipitates formed upon cooling of the reaction. After removalof the solvent, the content was dissolved into DCM and the organic phasewas washed with water. After removal of solvent, the solid wasrecrystalized from MeOH to give 11 g of 38 as a white solid.

Synthesis of Compound 39

To a solution of compound 38 (11 g, 36 mmol) in 200 mL acetic acid wasadded sodium cyanoborohydride (4 eq). The reaction was stirred for 30min, and after removal of solvents, the solid was partitioned betweensaturated sodium carbonate/DCM and the aqueous layer was extracted withDCM (3×). The combined organic layers was dried and evaporated. Theresidue was chromatographed with a silica gel column using ethyl acetatein hexane as elutant to give 9.5 gram crude product 39.

Synthesis of Compound 41

Compound 41 was synthesized from 40 following a procedure similar to thetransformation from 2 to 3 (Method 1).

Synthesis of Compound 42

Compound 42 was synthesized from 41 following procedures similar to thetransformation from 16 to 19 (Method 5).

Synthesis of Compound 43

Compound 43 was synthesized from 42 following a procedure similar to thetransformation from 7 to 8 (Method 2).

Chiral Resolution of 43

Compound 43 was resolved with a procedure similar to the resolution ofcompound 29. The first peak at was collected as enantiomer 43a and thesecond peak was collected as enantiomer 43b.

Synthesis of Compound 44

Compound 44 was synthesized from 43a following a procedure similar tothe transformation from 29 to 30 (Method 9).

Synthesis of Compound 45

To a cooled solution of compound 43 (5.5 g, 20.5 mmol), DMAP (1 mmol),diisopropylethylamine (2.0 eq) in 40 mL anhyd. DCM at 0° C. was addedacetyl chloride. The starting material disappeared in 30 min and thereaction mixture was washed with 0.5 N HCl. After removal of solvent,the residue was dissolved in 30 mL of anhyd. DCM followed by addition ofoxalyl chloride (3 eq) and 2 drops of DMF. The reaction was keptovernight under rt and solvent evaporated to give a crude product 45 asan oil, which was used for next step without further purification.

Synthesis of Compound 47

After evaporating solvent from the DCM solution of 45 three times, thecrude acid chloride was dissolved in 20 mL of DCM followed by additionof a 5 mL DCM solution of compound 39 with 2 eq ofdiisopropylethylamine. After the solution was stirred overnight at rt,the solvent was evaporated to give the crude product 46. After the crudeproduct was treated with 7N ammonia in methanol for 30 min, the solventwas removed and the residue chromatographed on a silica gel columneluted with ethyl acetate and hexane to give 5.1 g of product 47.

Synthesis of Compound 48

Compound 48 was synthesized from compound 47 following a proceduresimilar to the transformation from 9 to 11 (Method 3).

Synthesis of Compound 49

Compound 49 was synthesized from compound 48 following proceduressimilar to the transformation from 11 to 11a (Method 3).

Synthesis of Compound 50a

Compound 50a was synthesized following a procedure similar to thetransformation from 30 to 31 (Method 10).

Synthesis of Compound 51b

Compound 50a (98 mg, 2 mmol) was dissolved in MeOH and hydroxylaminehydrochloride (440 mg, 6.3 mmol) and DBU (1.76 mL, 11.8 mmol) wereadded. The reaction mixture was stirred at rt for 2 h. AcOH (680 μL,11.8 mmol) was added and the reaction mixture was concentrated todryness. The crude product was purified via silica gel chromatographyusing 95:5 CH₂Cl₂:MeOH as the mobile phase to give 12 mg of 51b.

¹H NMR (300 MHz, CDCl₃): δ 7.90 (m, 1H), 7.80 (m, 1H), 7.63 (s, 1H),7.58–7.50 (m, 1H), 7.46–7.43 (m, 1H), 6.89 (m, 2H), 6.64 (m, 2H), 5.28(s, 2H), 3.73–3.70 (m, 2H), 2.98 (s, 2H), 1.92 (m, 1H), 1.25–1.21 (m,2H), 0.81 (m, 3H).

Synthesis of Compound 52

To a mixture of compound 51 (0.5 gram) in 30 mL of methanol was addedsulfuric acid (1.5 eq) and the mixture was refluxed for 6 h. Afterremoval of the solvent, the residue was dissolved in DCM and thesolution was washed with sat sodium bicarbonate. The organic layer wasdried and solvent evaporated to give 0.5 g of product 52, which was usedwithout purification for next step.

Synthesis of Compound 53

To a solution of compound 52 (0.5 gram) in 20 mL of methanol was addedsodium borohydride (2 eq), and the mixture was stirred overnight. Afterthe removal of solvent, the residue was partitioned in DCM and water.The aqueous layer was extracted(3×) and the combined organic layer wasdried, solvent evaporated to give compound 53 (0.45 g) which was usedfor next step without purification.

¹H NMR (CDCl₃) δ 7.96 (d, 1H); 7.81 (d, 1H); 7.61 (m, 1H); 7.41 (m, 1H);7.21 (s, 1H); 5.13 (s, 2H); 2.20 (m, 1H); 1.06 (m, 4H).

Synthesis of Compound 54

To a solution of compound 53 (0.5 gram) in 20 mL of anhyd. DCM was addedthionyl chloride (2 eq), and the mixture was stirred for 30 min. Afterremoval of solvent, the residue was partitioned in DCM and water. Theaqueous layer was extracted(3×) and the combined organic layer wasdried, solvent evaporated to give compound 54 (0.55 g) which was usedfor next step without purification.

Synthesis of Compound 55

To a 1 mL DMF solution of 20 mg of 49 (0.036 mmol), 9 mg of 54 as a HClsalt (0.035 mmol) and 2 mg of tetrabutylammonium iodide was added with200 mg of potassium carbonate and the mixture was stirred overnight.After removal of DMF, the residue was chromatographed to give 23 mg ofproduct 55.

Synthesis of Compound 56

To a solution of compound 55 in 1 mL of DCM was added 5 eq oftriethylsilane and 1 mL TFA. The solution was let stand for 2 h and thesolvent evaporated. The residue was chromatographed with a C-30 reversephase HPLC eluted with 5–95% acetonitrile in water to give 15 mg of 56.

¹H NMR (CD₃OD): δ 8.08 (m, 1H); 7.95 (m, 1H); 7.75 (m, 1H); 7.55 (m,1H); 7.4 (s, 1H); 7.0–7.2 (m, 3H); 5.6 (s, 2H); 3.1–3.3 (m, 2H); 2.3 (m,1H); 2.15 (m, 1H); 1.55 (m, 1H); 1.45 (m, 1H); 1.05–1.2 (m, 4H).

Synthesis of Compound 57

Compound 57 was synthesized following procedures similar to thetransformation of 49 to 56 (Method 17).

¹H NMR (CD₃OD): δ 8.08 (m, 1H); 7.95 (m, 1H); 7.75 (m, 1H); 7.55 (m,1H); 7.4 (s, 1H); 7.0–7.2 (m, 3H); 5.6 (s, 2H); 3.61 (s, 3H); 3.0–3.25(m, 2H); 2.3 (m, 2H); 1.55 (m, 2H); 1.05–1.2 (m, 4H).

Synthesis of Resin 60

The mixture of 8.3 gram pre-swelled resin 58 (0.91 mmol/g) and 1.1 eq of59 as a HCl salt in 20 mL of 10:20:70 solvent mixture of HOAc:MeOH:THFwas agitated overnight. After the resin was washed with MeOH, THF andDCM, it was preswelled in 20 mL anhyd. DCM. After the mixture was cooleddown to 0° C., 15 equivalent of BH₃.Py and 23 eq of dichloroacetic acidwere added. After the reaction was agitated overnight, the resin waswashed with MeOH, THF and DCM and dried in vacuo to give resin 60.

Synthesis of Compound 61

Compound 61 was synthesized following procedures similar to thetransformation from 43 to 45 (Method 13).

Synthesis of resin bound compound 62

Compound 61 (150 mg, 0.46 mmol) was dissolved in 2 mL of anhyd DCM andthe solution was added to 178 mg of resin 60 with 0.2 mL of DIEA. Thefinal mixture was agitated for 12 h before the resin was washed with 20%piperidine in DMF followed by wash with combination of MeOH, DCM andTHF. The loading level of the final resin was determined to be 0.4mmol/g after cleavage with 75% TFA in DCM overnight.

Synthesis of Resin Bound Compound 63b and 63c.

To preswelled resin 62 (75 mg) with anhyd THF was added 5 eq of1,1′-(azodicarboxyl)dipiperidine, 5 eq of 2–3-dichlorobenzylalcohol and7 eq. of tributylphosphine in 3 mL of THF under nitrogen. The finalreaction mixture was heated to 70° C. with agitation overnight. Afterwashing with MeOH, DCM and THF, the resin was cleaved with 75% TFA inDCM for 2 h. The residue after removal of the solvent was purified witha C-18 reverse phase column eluted with 5–95% of MeCN in water to givedesired products 63b and 63c.

¹H NMR (CD₃OD) for 63b: δ 7.36–7.43 (m, 4H); 7.14–7.17 (m, 2H);6.86–6.88 (m, 2H); 5.03 (2H, s); 3.61 (3H, s); 2.96–3.20 (2H, m);2.23–2.27 (1H, m); 1.52–1.54 (2H, m).

¹H NMR (CD₃OD) for 63c: δ 7.17–7.23 (m, 4H); 6.89–6.93 (m, 2H);6.65–6.67 (m, 1H); 3.87 (s, 2H); 3.54 (3H, s); 2.86–3.12 (2H, m)2.18–2.22 (1H, m); 1.47–1.49 (2H, m).

Synthesis of Compound 64

To pre-swelled resin 62 (75 mg) was added 100 mg 5 micron 4 Å molecularsieves, 2 eq. of anhyd. copper acetate, and 5 eq of 1-naphthylboronicacid followed by 2 mL of anhyd. DCM. The reaction mixture was agitatedat rt overnight and the resin washed with THF. The above procedure wasrepeated before the resin was washed with MeOH, DCM, THF, and cleavedwith 75% TFA in DCM for 2 h. After removal of organic solvent, theresidue was purified with a C-18 reverse phase column eluted with 5–95%MeCN in water to give 4 mg of desired product 64.

¹H NMR (CD₃OD): δ 8.1 (m, 1H); 7.85 (m, 1H); 7.6 (m, 1H); 7.5 (m, 2H);7.37 (m, 1H); 7.23 (m, 2H); 6.95 (m, 2H); 6.86 (m, 1H); 4.07 (m, 2H);3.1–3.3 (m, 2H); 2.23 (m, 1H); 1.55 (m, 2H); 1.16 (m, 3H).

Synthesis of Compound 65

Compound 65 was synthesized from 19 following procedures similar totransformation from compound 9 to 11a (Method 3)

Synthesis of Compound 66

Compound 66 was synthesized from 65 following a procedure similar totransformation from compound 2 to 3 (Method 1) or 19a to 23 (Method 7).

Synthesis of Compound 67 and 68

Lawesson's reagent (250 mg, 0.62 mmol) was added to amide 66 (544 mg,1.2 mmol) in toluene and the reaction was refluxed for an hour beforeanother 0.5 equiv of Lawesson's reagent was added. The reaction washeated for one more hour and the mixture was diluted with DCM, washedwith a saturated sodium bicarbonate(3×) and water(3×). The organicextract was dried over sodium sulfate and concentrated. The crudematerial was purified via flash chromatography eluting with a 0–2% 2NNH₃/CH₃OH:CH₂Cl₂ gradient affording a 1:4 ratio of thioamide 67 tonitrile 68.

Synthesis of Compound 69

Compound 69 was synthesized from 68 following procedures similar to thetransformation of 7 to 10 (Method 2).

¹H NMR (CD₃OD): δ 8.45 (m, 1H); 8.16 (m, 3H); 7.97 (m, 1H) 7.3 (m, 2H);7.15 (m, 2H); 5.87 (s, 2H); 3.09 (s, 2H); 3.07 (s, 3H); 2.25 (m, 1H);1.6 (m, 2H).

Synthesis of Compound 70

A 50% aq. chloroacetaldehyde solution (0.100 mL, 0.79 mmol) andpotassium bicarbonate (80 mg, 0.8 mmol) was added to thioamide 67 (74mg, 0.16 mmol) in tetrahydrofuran. The solution was stirred overnight atroom temperature. The reaction was concentrated and the residue waspartitioned between DCM and water. The organic extracts were washed withwater (3×), dried over sodium sulfate and concentrated. The crudematerial was dissolved in DCM (2 mL) with diisopropylethylamine (0.056mL, 0.032 mL) and the solution was cooled to 0° C. beforetrifluoroacetic anhydride (0.040 mL, 0.03 mmol) was added. The reactionwas stirred at room temperature for 1.5 hr before it was concentrated.The residue was dissolved in DCM, washed with a saturatedbicarbonate(3×), and water (3×). The organic extracts were dried oversodium sulfate and concentrated. The crude material was purified viaflash chromatography eluted with 0–3% 2N NH₃ in CH₃OH/CH₂Cl₂ gradient toafford 70.

Synthesis of Compound 71

Compound 71 was synthesized following procedures similar to thetransformation of 7 to 10 (Method 2).

¹H NMR (CD₃OD): δ 8.45 (m, 1H); 8.10 (m, 2H); 8.08 (m, 1H); 7.97 (m, 1H)7.58 (m, 1H); 7.36 (m, 1H); 7.14 (m, 2H); 7.01 (m, 2H); 5.80 (s, 2H);3.3–3.5 (m,); 2.95 (s, 3H); 2.25 (m, 1H); 1.83 (m, 1H); 1.77 (m, 1H).

Synthesis of Compound 72

Hydroxylamine hydrochloride (186 mg, 2.7 mmol) and diisopropylethylamine(0.47 mL, 2.7 mmol) were combined in ethanol and agitated for 30 minutesbefore compound 69 (105 mg, 0.25 mmole) was added to the solution. Thereaction was irradiated in a microwave for five minutes at 100° C.followed by addition of 10 eq of both hydroxylamine hydrochloride anddiisopropylethylamine. The reaction was irradiated with a microwave forfive additional minutes at 100° C. before the reaction was concentrated.The residue was dissolved in DCM and washed with a saturated aqueoussolution of sodium bicarbonate (3×) and water (3×). The organic extractswere dried over sodium sulfate and concentrated to afford 113 mg ofcrude material. Pyridinium-p-toluenesulfonate (63 mg, 0.25 mmol) andtriethylorthoformate (1 mL, 6.0 mmol) were added to the above crudematerial in ethanol followed by irradiation in a microwave for 5 minutesat 100° C. The reaction was concentrated and the resulting oil wasdissolved in DCM, washed with a sat sodium bicarbonate (3×) and water(3×). The organic extracts were dried over sodium sulfate andconcentrated. The crude material was chromatographed with a silica gelcolumn eluted with a 0–3% 2N NH₃ in CH₃OH/CH₂Cl₂ gradient to afford 72.

Synthesis of Compound 73

Compound 73 was synthesized from 72 following procedures similar to thetransformation of 7 to 10 (Method 2).

¹H NMR (CD₃OD): δ 9.05 (s, 1H); 8.41 (m, 1H); 8.10 (m, 3H); 7.91 (m,1H); 7.25 (m, 2H); 7.02 (m, 2H); 5.80 (s, 2H); 3.3–3.5 (m,); 2.95 (s,3H); 2.25 (m, 1H); 1.75 (m, 1H); 1.64 (m, 1H).

Synthesis of Compound 74

Compound 74 was synthesized from 19a following procedures similar to thetransformation from 6b to 9 (Method 2).

Synthesis of Compound 75

Compound 75 was synthesized from 74 following procedures similar to thetransformation from 9 to 11a (Method 3).

Synthesis of Compound 76

Amide 75 (10 mg) was dissolved in 1 mL of N,N′-dimethylforamide-dimethylacetal and irradiated with a microwave at 100° C. for 5 minutes. Afterthe solution was concentrated, the residue was dissolved in glacialacetic acid before hydrazine monohydrate was added. The reaction wasirradiated again with a microwave for 100° C. for 5 minutes and thesolution was concentrated. The final product mixture was purified viareverse phase HPLC eluting with a 0–95% CH₃CN/H₂O gradient to givecompound 76.

¹H NMR (CD₃OD): δ 8.35 (m, 1H); 8.7–8.17 (m, 4H); 7.91 (m, 1H); 7.10 (m,2H); 6.98 (m, 2H); 5.76 (s, 2H); 3.3–3.5 (m,); 2.95 (s, 3H); 2.08 (m,1H); 1.68 (m, 2H).

Synthesis of Compound 77

Compound 77 was synthesized from 28 following a procedure similar totransformation from compound 2 to 3 (Method 1) or 19 to 23 (Method 7).

Synthesis of Compound 78

Sodium borohydride (48 mg, 1.3 mmol) was added to a solution of 77 (60mg, 0.13 mmol) in methanol under reflux. Additional amount of sodiumborohydride was added until the starting material is completelyconsumed. After the reaction was concentrated, the residue waspartitioned between DCM and water. The aqueous solution was extractedwith DCM (3×) and the combined organic layers were washed with a sat.solution of NaHCO₃ (3×), H₂O (3×), dried over sodium sulfate. Afterremoval of solvent, the crude material was purified via flashchromatography eluted with ethyl acetate/ hexane to afford 78.

Synthesis of Compound 79

Compound 78 was treated with 30% trifluoroacetic acid in DCM (1–2 mL)for 2.5 h followed by removal of solvent. The residue was treated with2N NH₃ in methanol followed by removal of solvent. The residue was usedfor the synthesis of compound 79 following procedures similar to thetransformation of 8 to 10 (Method 2).

¹H NMR (CD₃₀OD) of 79: δ 8.35 (m, 1H); 8.13 (m, 1H); 8.01 (m, 1H); 7.96(s, 1H); 7.84 (m, 1H); 7.21 (m, 2H); 7.05 (m, 2H); 5.76 (s, 2H); 3.2–3.3(m,); 2.93 (m, 5H); 1.54 (m, 1H); 1.29 (m, 1H); 0.96 (m, 1H).

Synthesis of Compound 80 and 81

To a 2 mL solution of 0.264 g (1 mmol) of 29 was added N-chlorosuccinate(1.1 eq) and the solution was stirred for 2 h. After removal of solvent,the product mixture was purified via a C-18 reverse phase column elutedwith 5–95% acetonitrile in water get pure 0.20 g of 80 and 0.05 g of 81.

Synthesis of Compound 82

Compound 82 was synthesized from 81 following a procedure similar totransformation from 29 to 30 (Method 9) and 30 to 33 (Method 10).

¹H NMR (CDCl₃): δ 8.10 (m, 1H); 7.85 (m, 1H); 7.70 (m, 1H); 7.54 (m,1H); 7.26 (m, 2H); 6.98 (m, 1H); 6.71 (m, 1H); 5.41 (s, 2H); 4.1 (m,2H); 3.14 (m, 2H); 2.73 (s, 3H); 2.23 (m, 1H); 1.65 (m, 1H); 1.56 (m,1H); 1.16 (m, 3H).

Synthesis of Compound 83 and 84

Compounds 83 and 84 were synthesized from 29 following proceduressimilar to transformation of 29 to 80 and 81 (Method 28).

Synthesis of Compound 85

Compound 85 was synthesized from 84 following a procedure similar totransformation from 29 to 30 (Method 9) and from 30 to 33 (Method 10).

¹H NMR (CD₃OD): δ 8.41 (m, 1H); 8.06–8.22 (m, 3H); 7.94 (m, 1H); 7.54(m, 1H); 7.26 (m, 2H); 5.88 (s, 2H); 4.07 (m, 2H); 2.98–3.25 (m, 2H);2.87 (s, 3H); 2.23 (m, 1H); 1.54 (m, 2H); 1.16 (m, 3H).

Synthesis of Compound 86

Compound 86 was synthesized following a procedure similar to thetransformation of 62 to 63a (Method 20).

Synthesis of Compound 87

A mixture of resin 86 (0.070 g, ˜0.7 mmol/g) and 1-methyl piperazine(0.5 mL) in toluene (1 mL) was agitated at 80° C. for 68 hours. Theliquid was drained, and the resin was washed with an alternating cycleof CH₂Cl₂ (3×), THF (3×), and MeOH (3×). The resin was dried undervacuum for 10 minutes. The cartridge was charged with 75% TFA/CH₂Cl₂ andagitated at room temperature for 24 hours. The liquid was collected, andthe resulting black resin was washed with CH₂Cl₂ (3×). The solvent wasremoved, and the residue was purified by reverse phase HPLC to provide87.

¹H NMR (CD₃OD): δ 7.92–7.90 (m, 1H), 7.75–7.73 (m, 1H), 7.63–7.58 (m,1H), 7.37–7.34 (m, 2H), 7.21–7.19 (m, 2H), 6.99–6.97 (m, 2H), 5.48 (s,2H), 4.09–3.98 (m, 6H), 3.29–3.27 (m, 4H), 3.22–3.18 (m, 1H), 3.04–3.00(m, 1H), 2.86 (s, 3H), 2.28–2.23 (m, 1H), 1.55–1.53 (m, 2H), 1.17–1.13(m, 3H).

Synthesis of Compound 88

Compound 88 was prepared from 49 following a procedure similar to thetransformation of 2 to 3 (Method 1).

Synthesis of Compound 89

A mixture of 88 and pyrrolidine in DME was irradiated in a microwave(100° C. for 25 minutes). The mixture was concentrated and purified byreverse phase HPLC to provide the product 89.

Synthesis of Compound 90

Compound 90 was prepared from 89 following a procedure similar to thetransformation from 55 to 56 (Method 17).

¹H NMR (CD₃OD): δ 8.06–8.03 (m, 1H), 7.95–7.93 (m, 1H), 7.83–7.80 (m,1H), 7.57–7.53 (m, 1H), 7.40–7.38 (m, 1H), 7.23–7.19 (m, 1H), 7.09–7.02(m, 2H), 5.63 (s, 2H), 3.82–3.78 (m, 4H), 3.63 (s, 3H), 3.22–3.18 (m,1H), 3.06–3.02 (m, 1H), 2.31–2.05 (m, 5H), 1.58–1.52 (m, 2H).

Synthesis of Compound 93

To a 250 mL round bottom flask containing aniline (1.8 mL, 20 mmol) wasadded concentrated HCl (5 mL) followed by chloranil (4.9 g 20 mmol) andn-BuOH. The mixture was heated to reflux and stirred vigorously at whichtime a solution of pentenal (2.4 mL, 24.5 mmol) in n-BuOH (2 mL) wasadded slowly over a 45 minute period. After the addition was complete,the mixture was refluxed for another 20 minutes and then cooled to roomtemperature. The mixture was diluted with ethyl acetate, and the organiclayer was separated which was discarded. The aqueous phase wasbasicified with a saturated solution of Na₂CO₃ and extracted with ethylacetate (3×). The collected organic layers were dried (Na₂SO₄),filtered, and concentrated. The brown oil was purified by flashchromatography to give compound 93.

Synthesis of Compound 94

To a solution of 93 (0.927, 5.9 mmol) in MeOH (12 mL) and H₂O (6 ml) wasadded concentrated H₂SO₄ (0.300 mL) followed by iron powder (0.100 g,1.8 mmol). The reaction was evacuated and flash with nitrogen (3×) andthen cooled to 0° C. Hydroxylamine-O-sulfonic acid (2.0 g, 17.7 mmol)was added and the resulting mixture was stirred at 0° C. for 15 minutesand at room temperature for 5 hours. The mixture was basicified with asaturated Na₂CO₃ solution and diluted with CH₂Cl₂. The organic layer wasremoved, and the aqueous layer was extracted with CH₂Cl₂ (4×). Thecombined organic layers were dried (Na₂SO₄), filtered, and concentrated.The residue was purified by flash chromatography to give compound 94.

Synthesis of Compound 95

Compound 95 was synthesized from 94 following a procedure similar to thetransformation of 53 to 54 (Method 16).

Synthesis of Compound 96

Compound 96 was synthesized from 95 following a procedure similar to thetransformation of 47 to 57 (Method 18).

¹H NMR (CD₃OD): δ 8.10 (m, 1H), 8.03 (m, 1H), 7.79 (m, 1H), 7.67 (s,1H), 7.63 (m, 1H), 7.12 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H); 5.63 (s,2H), 3.57 (s, 3H), 3.0–3.2 (m, 2H), 3.0 (m, 2H), 2.26 (m, 1H); 1.52 (m,2H); 1.35 (m, 3H).

Synthesis of Compound 97

Compound 97 was synthesized from 29a following procedures similar to thetransformation of 43 to 47 (Method 13) and 47 to 57 (Method 18).

Synthesis of Compound 98

Compound 98 was synthesized from 97 following procedures similar to thetransformation of 50 to 56 (Method 17).

¹H NMR (CD₃OD): δ 9.48 (s, 1H); 9.07 (m, 1H); 8.80 (m, 1H); 8.30 (s,1H), 8.21 (m, 2H), 7.98 (m, 1H), 7.87 (s, 1H), 7.73 (m, 1H), 7.22 (m,2H), 7.04 (m, 2H), 5.70 (s, 2H), 4.04 (m, 2H), 2.95–3.22 (m, 2H), 2.24(m, 1H), 1.51 (m, 2H); 1.12 (m, 3H).

Synthesis of Compound 99

Compound 99 was synthesized from 30 following procedures similar to thetransformation from 30 to 32 (Method 10).

Synthesis of Compound 100

Compound 99 (0.07 g, 0.17 mmol), (L)-serine methyl ester (26 mg, 0.17mmol), and N-methyl morpholine (51 mg, 0.5 mmol) were dissolved in DMF.After addition of EDCl (48 mg, 0.25 mmol), the reaction mixture wasstirred overnight at rt. The reaction mixture was diluted with EtOAc,washed with water, and concentrated. The crude product was purified viasilica gel chromatography using a 2:1 EtOAc:Hexanes mobile phase to give58 mg of compound 100.

Synthesis of Compound 101

Compound 101 was synthesized from 100 following a procedure similar tothe transformation of 50a to compound 51b (Method 15).

¹H NMR (300 MHz, CD₃OD): δ 8.08 (m, 1H), 7.98 (m, 1H), 7.74 (m, 1H),7.57 (m, 2H), 7.18 (m, 2H), 6.95 (m, 2H), 5.54 (s, 2H), 4.4 (m, 1H),4.04 (m, 2H); 3.72 (m, 2H); 2.94–3.22 (m, 2H), 2.70 (s, 3H); 2.51 (m,1H), 1.52 (m, 2H), 1.14 (m, 3H).

Synthesis of Compound 103

Compound 103 was synthesized from compound 102 following proceduressimilar to the transformation from 16 to 19 (Method 5).

Synthesis of Compound 104

Compound 104 was synthesized from 103 following procedures similar tothe transformation from 6 to 10 (Method 2).

¹H NMR-(CD₃CN): δ 7.41–7.61 (m, 5H), 7.25 (m, 1H), 6.92 (m, 3H), 5.17(s, 2H), 3.67 (s, 3H), 3.08–3.33 (m, 2H), 2.35 (m, 1H), 1.64 (m, 1H);1.56 (m, 1H).

Synthesis of Compound 107

To a solution of methyl 2-(bromomethyl)acrylate 105 (2.0 mL, 16.6 mmol)and m-nitrophenylboronic acid 106 (3.0 g, 17.9 mmol) in toluene (150 mL)was added Pd(dppf)Cl₂.CHCl₃ (0.978 g, 1.34 mmol) and aqueous 3N K₂CO₃(16 mL). The mixture was heated to reflux and stirred for 1 hour. Thesolution was cooled to room temperature and diluted with 1N NaOH (150mL) and EtOAc (150 mL). The aqueous layer was removed, and the organicphase was washed with 1N NaOH (2×). The organic phase was dried(Na₂CO₃), filtered, and concentrated. The mixture was purified by flashchromatography to furnish compound 107 (0.880 g).

Synthesis of Compound 108

Compound 108 was synthesized from 107 following a procedure similar tothe transformation of 4 to 5 (Method 1).

Synthesis of Compound 109

A mixture of Compound 108 (0.450 g, 1.34 mmol) and 10% Pd/C (0.120 g) inMeOH was stirred at room temperature under an atmosphere of H₂ for 1.5hours. The mixture was filtered through a pad of silica and concentratedto give the aniline, which was used for next step without purification.To a solution of crude aniline (prepared above) and pyridine (0.230 mL,2.84 mmol) in CH₂Cl₂ (20 mL) was added p-methoxyphenyl sulfonylchloride(0.284 g, 1.37 mmol). The mixture was stirred for 2 hours and thenconcentrated. The oil was purified by flash chromatography to providecompound 109 (0.541 g) as foam.

Synthesis of Compound 111

To a solution of Compound 109 (0.147 g, 0.31 mmol) and K₂CO₃ (0.135 g,0.98 mmol) in DMF (0.700 mL) was added Mel (0.021 mL, 0.34 mmol). Thereaction was stirred for 1.5 hours under nitrogen, quenched with H₂O,and diluted with EtOAc. The organic layer was separated, and the aqueousphase was extracted with EtOAc (3×). The combined organics were washedwith H₂O (2×), dried (Na₂SO₄), filtered, and concentrated to providecompound 111 (0.141 mg).

Synthesis of Compound 112

Compound 112 was synthesized from 111 following procedures similar tothe transformation of 7 to 10 (Method 2).

¹H NMR (CDCl₃): δ 7.50 (m, 2H), 7.14–7.17 (m, 3H), 6.92 (m, 2H), 6.57(m, 1H), 3.86 (s, 3H), 3.73 (m, 1H), 3.70 (s, 3H), 3.10 (s, 3H),3.01–2.97 (m, 1H), 1.71–1.59 (m, 2H), 1.27–1.24 (m, 1H).

Synthesis of Compound 110

Compound 110 was synthesized from 109 following procedures similar tothe transformation of 7 to 10 (Method 2).

¹H NMR (CDCl₃) of 110: δ 7.67 (m, 2H), 7.09–6.97 (m, 3H), 6.88 (m, 2H),6.72 (m, 1H), 3.81 (s, 3H), 3.62 (s, 3H), 3.34 (m, 1H), 3.02 (m, 1H),2.41–2.37 (m, 1H), 1.65–1.62 (m, 1H), 1.55–1.52 (m, 1H).

Synthesis of Compound 113

Compound 113 was synthesized from 114 following procedures similar tothe transformation of 107 to 110 (Method 36).

¹H NMR (CD₃OD): δ 7.65–7.63 (m, 2H), 7.10–7.08 (m, 2H), 6.97–6.94 (m,4H), 4.03–3.98 (m, 2H), 3.82 (s, 3H), 3.16–3.12 (m, 1H), 3.02–2.98 (m,1H), 2.27–2.24 (m, 1H), 1.53–1.50 (m, 2H), 1.08–1.05 (m, 3H).

Synthesis of Compound 115

Compound 115 was synthesized from 114 following procedures similar tothe transformation of 107 to 112 (Method 36).

¹H NMR (CD₃OD): δ 7.45–7.42 (m, 2H), 7.20–7.18 (m, 2H), 7.02–6.96 (m,4H), 4.09–4.04 (m, 2H), 3.87 (s, 3H), 3.23–3.20 (m, 1H), 3.13–3.10 (m,1H), 3.12 (s, 3H), 2.32–2.28 (m, 1H), 1.57–1.54 (m, 2H), 1.14 (m, 3H).

Synthesis of Compound 116

To a TFA solution of 219 mg (1.09 mmol) compound 29 was added 2 eq ofSelectfluor and the solution was stirred overnight. After evaporation ofsolvent, the residue was chromatographed on a C-18 reverse phase columnto give 24 mg of compound 116.

Synthesis of Compound 117

Compound 117 was synthesized from 116 following procedures similar tothe transformation of 29 to 30 (Method 9) and then 30 to 33 (Method 10).

¹H NMR (CD₃OD): δ 8.19 (m, 1H), 8.05 (m, 1H), 7.87 (m, 1H), 7.75 (s,1H); 7.70 (m, 1H); 7.15 (m, 1H); 7.06 (m, 1H); 7.00 (m, 1H); 5.70 (s,2H), 4.06 (m, 2H), 3.02–3.21 (m, 2H), 2.79 (s, 3H), 2.26 (m, 1H), 1.53(m, 2H), 1.14 (m, 3H).

Synthesis of Compounds 119 and 120

To a solution of 118 (0.63 g, 3.30 mmol) in 8 mL of anhyd. THF at −78°C. was added 1.8 mL of 2 M LDA in THF, and the reaction mixture wasstirred at −78° C. for 1 h. A solution of 4-benzyloxybenzylbromide (0.94g, 3.39 mmol) in 2 mL of anhyd. THF was added via addition funnel. Thereaction mixture was stirred and allowed to warm to 23° C. overnight.The reaction was quenched with 5 mL of saturated NH₄Cl and extract with20 mL of diethyl ether. The organic solution was washed with 5 mL ofbrine, dried (MgSO₄), filtered, and concentrated in vacuo. Purificationby flash silica gel chromatography gave 0.11 g (9%) of compound 119 and0.40 g (31%) of compound 120.

Synthesis of Compound 121

Compound 121 was synthesized from 119 following procedures similar tothe transformations of 18 to 19 (Method 5) and 30 to 33 (Method 10).

¹H NMR (DMSO): δ 10.74 (s, 1H), 8.79 (s, 1H), 8.07 (m, 1H), 7.95 (m,1H), 7.59–7.74 (m, 1H), 7.53–7.58 (m, 1H), 7.51 (s, 1H), 7.05 (m, 2H),6.96 (m, 2H), 5.53 (s, 2H), 3.63 (m, 1H), 3.46 (s, 3H), 3.05 (m, 1H),2.63 (s, 3H), 1.97 (s, 1H), 1.34 (s, 3H), 1.03 (s, 3H).

Synthesis of Compounds 122 and 123

Compound 122 was prepared from isatin according to the proceduredescribed by H. W. Tsao, U.S. Pat. No. 4,267,33; May 12, 1981. The acidwas reduced to the alcohol using cyanuric fluoride and sodiumborohydride according to the procedure in G. Kokotos and C. Noula J.Org. Chem. 1996, 61, 6994–6996.

Compound 124 was prepared according to the procedure in A. G. Taveras etal US Patent 2002 U.S. Pat. No. 6,327,47.

Compound 125 was prepared according to a procedure similar to the onedescribed by F. J. Lotspeich J. Org. Chem. 1967, 32, 1274–1277.

Synthesis of Compound 128

Compound 128 was synthesized from 127 following a procedure similar tothe transformation of 19a to 23.

Synthesis of Compound 129

A solution of compound 128 (4.0 g, 11.73 mmol) in anhyd CH₂Cl₂ (60 mL)was cooled to 0° C. with a ice-water bath before PBr₃ (1.1 mL, 11.73mmol, in 5 mL anhyd CH₂Cl₂) was added. The solution was stirred at 0° C.for 4 hours and at rt for 12 hours before it was poured into a coldsaturated aq NaHCO₃ (250 mL) with stirring. The aq layer was extractedwith CH₂Cl₂ (4×). The combined organic layers were washed with brine(100 mL), dried over anhyd Na₂SO₄, and concentrated. The residue wasdried under vacuum for 4 hours to give compound 129 (4.3 g, 91%).

Synthesis of Compound 131 and 132

To a 100 mL round bottom flask was added diisopropyl amine (1.0 mL, 7.16mmol) and anhyd THF (10 mL). The solution was cooled to −40° C. beforen-BuLi (1.45 M, 4.5 mL, 6.52 mmol) was added dropwise via a syringe. Thesolution was gradually warmed up to −20° C. in 20 minutes before it wascooled to 31 78° C. The above solution was added to a solution ofcis-dimethyl 1,2-cyclobutane diester 130 (1.02 g, 5.92 mmol) in anhydTHF (10 mL) at −78° C. via a cannula. The solution was stirred at −78°C. for an hour followed by addition of compound 129 (1.9 g, 4.74 mmol)in anhyd THF (5 mL). The solution was stirred at −78° C. for 4 h, andallowed to gradually warmed up to room temperature overnight before sataq NH₄Cl (50 mL) was added. The aq layer was extracted with EtOAc(3×)and the combined organic layers were dried over anhyd Na₂SO₄, andconcentrated. The residue was chromatographed to give compounds 131 and132 (110 mg).

Synthesis of Compound 133

Compound 133 was synthesized from 132 following a procedure similar tothe transformation of 50a to 51b(Method 15).

¹H-NMR (CD₃OD, 300 MHz): δ 8.16 (m, 2H), 8.08 (m, 3H), 7.81 (m, 1H),7.65 (m, 1H), 7.58–7.50 (m, 3H), 7.06 (m, 2H), 7.01 (m, 2H), 5.66 (s,2H), 3.63 (s, 3H), 3.18 (m, 1H), 3.11 (m, 1H), 3.05 (m, 1H), 2.37 (m,2H), 2.13 (m, 1H), 1.94 (m, 1H).

Synthesis of Compound 135

Compound 135 was synthesized from 134 following a procedure similar tothe transformation of 51 to 53 (Method 16).

Synthesis of Compound 136

Compound 135 (1.45 g/10.1 mmol) was dissolved in 20 mL of toluene andmorpholine (8.6 mL) was added. The reaction mixture was stirred under N₂at 110 C over the weekend then concentrated to give 8.2 g of a yellowoil which was purified to give compound 136.

Synthesis of Compound 137

Compound 137 was synthesized from 136 following a procedure similar tothe transformation of 53 to 54 (Method 16).

Table 1 below provides preferred compounds of the present invention andassociated LCMS and/or HNMR data.

TABLE 1 Rt M + 1 Structures (min) (Obs) 1H NMR Method A

4.56 342 1H NMR (CD3CN): d 7.6–7.4 (m,5H); 7.3 (m, 1H); 6.95 (m, 3H);5.2(m, 2H); 3.7 (s, 3H); 2.6 (m,1H); 2.05 (m, 1H); 1.85 (m,1H). 2 B

2.91 266 1H NMR (CD3CN): d 7.35 (m, 1H);6.95 (m, 3H); 3.9 (s, 3H); 3.71(s,3H); 2.6 (m, 1H); 2.05 (m, 1H);1.85 (m, 1H). 2 C

307 2A D

392 2AB E

3.46 327 1H NMR (CD3CN): d 7.6–7.35(m, 5H); 7.4 (m, 1H); 7.05 (m,3H);6.4 (br s, 1H);5.85 (br s, 1H); 5.2 (m,2H); 2.6 (m, 1H); 1.9(m, 1H);1.75 (m, 1H). 3 F

2.05 251 1H NMR (CD3CN): d 7.4 (m, 1H);7.02 (m, 3H); 6.1 (br s, 1H);5.75(br s, 1H); 3.9 (s,3H); 2.6 (m, 1H), 1.9(m, 1H); 1.75 (m, 1H). 2ABC;3 G

383 4A′;2BC;3AB H

5.56 397 4A′ I

4.31 384 4A′;3A J

412 1H NMR (CDCl3): d 7.3–7.5(m,5H); 7.20 (m, 2H); 6.9 (m,2H); 5.0 (s,2H); 4.1(m, 2H);3.15(m, 0.3H); 2.5(m, 0.5 H); 2.05 (m, 1H);1.7–1.9 (m,1.2 H);1.3 (br. s, 3 H) 1.2 (m, 3H);1.1 (br. s, 6 H) 4A′ K

4.66 341 4A′;2B L

411 5AB M

4.26 395 6 N

3.86 355 6 O

2.45 496 7A; 6 P

1.95 497 7A; 6 Q

3.64 492 7A; 6 R

3.98 520 7A; 6 S

2.25 448 7A; 6 T

3.88 462 7A; 6 U

3.68 448 7A; 6 V

2 420 7A; 6 W

3.84 462 7A; 6 X

2.6 510 7A; 6 Y

1.95 497 7A; 6 Z

3.84 462 7A; 6 AA

3.95 474 7A; 6 AB

4.11 510 7A; 6 AC

4.32 524 7A; 6 AD

2.5 488 7A; 6 AE

2.35 489 7A; 6 AF

4.08 482 7A; 6 AG

2.55 510 7A; 6 AH

4.41 431 1H NMR (CD3CN/D2O, 2:1): d7.29–7.44 (m, 6H),7.14–7.07 (m, 4H),6.846.81 (m, 4H), 5.03 (s, 2H),4.22–4.13 (m, 2H), 3.12–2.93(m, 2H),2.07–2.03 (m,1H), 1.49–1.46 (m, 1H),1.40 1.38 (m, 1H). 6 AI

3.91 462 7A; 6 AJ

3.66 424 6 AK

3.61 432 6 AL

3.61 432 6 AM

4.61 445 6 AN

4.41 461 6 AO

4.01 369 6 AP

4.46 449 6 AQ

4.56 423 6 AR

4.56 445 6 AS

4.41 447 6 AT

4.56 445 6 AU

3.78 518 7A; 6 AV

4.18 568 7A; 6 AW

3.68 460 7A; 6 AX

3.48 446 7A; 6 AY

3.21 489 7A; 6 AZ

341 5AB;2B BA

492 34 BB

554 34 BC

4.01 406 7AB BD

3.76 421 7 BE

3.76 421 7 BF

3.96 318 1H NMR (CD3CN): d 7.15 (m,2H), 6.84 (m, 2H), 4.64–4.62(m, 2H),3.58 (s, 3H), 3.15–2.94 (m, 2H), 2.22–2.18(m, 1H), 1.83–1.81 (m,3H),1.52–1.46 (m, 2H). 7 BG

4.71 356 1H NMR (CDCl3): d 7.42–7.31(m, 5H), 7.12 (m, 2H), 6.86 (m,2H),5.01 (s, 2H), 3.63 (s,3H), 3.20–3.09 (m,2H), 2.17 (m, 1H), 1.64–1.58(m,2H) 7 BH

3.96 406 7AB BI

5.05 449 8AB BJ

2.65 449 8AB BK

2.8 463 8AB BL

2.15 434 1H NMR (CD3OD): d 8.42–8.40(m, 1H), 8.19–8.09 (m,3H), 7.96–7.92(m, 1H), 7.14–7.05 (m, 4H), 5.82 (s, 2H),3.07 (s, 2H), 3.01 (s, 3H),2.99(s, 3H), 2.82 (s, 3H), 1.91–1.88(m, 1H), 1.54–1.51 (m, 1H),1.37–1.34(m, 1H). 8AC BM

3.58 469 10AB;7C;8A; 2D BN

3.36 407 8A; 2D BO

488 15A;10BD BP

531 15A;10BD BQ

551 1H NMR (CD3OD): δ 8.02–8.18(m, 5H); 7.72–7.82(m, 2H);7.42–7.68(m,4H); 7.04–7.18(m,2H); 6.96–7.04(m, 2H); 5.59(s,2H); 3.82–4.02(m,2H);3.44–3.70(m, 2H); 2.96–3.20(m, 4H); 1.82–1.96 (m, 1H);1.50–1.62(m,1H);1.28–1.40(m, 1H). 10ABD BR

565 1H NMR (CD3OD): δ 8.0–8.18(m, 5H); 7.72–7.80 (m, 1H);7.56–7.62(m,1H); 7.42–7.56(m,3H); 7.14–7.26 (m, 2H); 6.98–7.08 (m, 2H); 5.55 (s,2H);3.08–3.26 (m, 2H); 2.76–2.92 (m, 4H); 2.24–2.42(m,2H);2.04–2.16(m,1H); 1.40–1.56 (m, 2H);1.16–1.40(m, 3H); 0.76–0.96 (m,2H).10ABD BS

4.88 497 1H NMR (CD3OD): δ 8.54–8.51(m, 2H), 8.44–8.42 (m,1H),8.24–8.20(m, 1H), 8.13–8.11 (m,2H), 8.05–8.01 (m, 1H), 7.83–7.75 (m,3H), 7.287.25 (m, 2H), 7.13–7.10 (m, 2H),5.95 (s, 2H), 4.08–4.02 (m,2H),3.24–3.20 (m, 1H), 3.04–3.00(m, 1H), 2.28–2.24 (m, 1H),1.56–1.54 (m,2H), 1.161.12 (m, 3H). 10ABC BT

5.22 420 10ABC BU

5.15 420 10ABC BV

4.71 449 1H NMR(400 MHz, CD3OD): d8.14–8.02 (m, 2H); 7.79–7.74(m, 1H);7.62–7.58 (m, 2H);7.22–7.20 (m, 2H); 7.00–6.98 (m,2H); 5.57 (s, 2H);4.08–4.03(m, 2H), 3.22–3.18(m, 1H), 3.03–2.96 (m, 3H);2.27–2.24 (m, 1H);1.55–1.53 (m, 2H); 1.39–1.34 (m, 3H),1.16 (m, 3H). 10ABC BW

3.11 406 8AC BX

3.61 421 1H NMR (CD3CN): d 8.38 (m,1H), 8.28 (m, 1H), 8.06–8.02(m, 2H),7.907.86 (m, 1H), 7.23 (d, 2H), 7.04(d, 2H), 5.72 (s, 2H), 3.59 (s,3H),3.16–2.99 (m, 2H), 2.96 (s,3H), 2.25–2.21 (m,1H), 1.54–1.47 (m, 2H) 7 BY

498 1H NMR(400 MHz, CD3OD): d9.48 (s, 1H); 9.07 (m, 1H); 8.80(m, 1H);8.30 (s, 1H), 8.21 (m,2H), 7.98 (m, 1H), 7.87 (s, 1H),7.73 (m, 1H), 7.22(m, 2H), 7.04(m, 2H), 5.70 (s, 2H), 4.04 (m,2H), 2.95–3.22 (m, 2H),2.24(m, 1H), 1.51 (m, 2H); 1.12 (m,3H). 10ABC BZ

3.71 485 10ABD CA

435 1H NMR(300 MHz, CD3OD): δ8.01 (m, 1H), 7.96 (m, 1H),7.74–7.69 (m,1H), 7.57–7.52 (s,1H), 7.19 (m, 2H), 6.943 (m,2H), 5.47 (s, 2H), 4.05(m, 2H),3.29–3.02 (m, 2H), 2.66(s, 3H), 2.30–2.20 (m, 1H), 1.60–1.48 (m,2H), 1.10 (m, 3H). 15 CB

507 15 CC

489 15 CD

507 15 CE

474 15A;10B CF

519 15 CG

518 15 CH

469 15 CI

510 15 CJ

416 15 CK

474 15 CL

573 15 CM

506 15A CN

3.71 453 1HNMR(400 MHz, CD3OD): d7.97–7.92 (m, 1H), 7.82–7.80(m, 1H),7.677.64 (m, 1H), 7.39–7.34 (m, 2H),7.21 7.02 (m, 3H), 5.57 (s,2H),3.31–3.29 (m, ) 2.19–2.14 (m,1H), 1.55–1.51 (m,1H), 1.46–1.43 (m,1H), 14, 31 CO

3.61 438 1HNMR(400 MHz, CD3OD): d8.16–8.04 (m, 2H), 7.86–7.82(m, 1H),7.74 (s, 1H), 7.69–7.65(m, 1H), 7.18–7.00(m, 3H), 5.65 (s, 2H),3.26–3.13(m, 2H), 3.07–3.02 (m, 2H), 2.18–2.14 (m, 1H), 1.56–1.53(m,1H), 1.46–1.37 (m, 4H). 17 CP

4.78 486 1H NMR(400 MHz, CD3OD): d8.35 (m, 2H); 8.3 (m, 1H); 8.15(m,2H); 8.05 (m, 1H); 7.85 (m, 1H);7.65 (m. 3H); 7.25 (m,, 1H); 7.0–7.15(m, 2H); 5.95 (s, 2H); 3.1–3.3 (m, 2H); 2.15 (m, 1H);1.55 (m, 1H); 1.45(m, 1H). 17 CQ

3.84 487 1H NMR(400 MHz, CD3OD): d9.4 (br. s, 1H); 8.7–8.9 (m,2H);8.15–8.25(m, 3H); 8.1 (s,1H); 7.78–7.85(m, 2H); 7.6–7.7(m,2H);7.0–7.25(m, 3H); 5.6(s, 2H);3.1–3.25(m, 2H); 2.15(m, 2H);1.5(m, 1H);1.45(m, 1H). 17 CR

3.64 452 1H NMR(400 MHz, CD3OD): d8.15(m, 1H); 8.05 (m, 1H); 7.75(m,1H); 7.6(m, 2H); 6.95–7.2(m, 3H); 5.62(s, 2H); 3.1–3.15(m,2H); 2.95 (m,2H); 2.15 (m, 1H);1.8 (m, 2H); 1.55 (m, 1H); 1.45(m, 1H); 1.0 (m, 3H).17 CS

487 17 CT

2.84 424 1H NMR(400 MHz, CD3OD): d8.41(m, 1H); 8.1–8.2 (m, 3H);7.95 (m,1H); 7.25 (m, 1H); 7.05–7.15 (m, 2H); 5.95 (s, 2H); 3.1–3.3 (m, 2H);3.02 (s, 3H);2.18 (m, 1H); 1.55 (m, 1H);1.45 (m, 1H). 12;10ABD CU

4.01 450 1H NMR (CD3OD): δ 8.08 (m,1H); 7.95 (m, 1H); 7.75 (m, 1H);7.55(m, 1H); 7.4 (s, 1H);7.0–7.2 (m, 3H); 5.6(s, 2H); 3.1–3.3 (m, 2H); 2.3(m, 1H);2.15(m, 1H); 1.55(m, 1H);1.45(m, 1H); 1.05–1.2 (m, 4H). 17 CV

3.04 424 17 CW

4.48 520 17 CX

4.01 570 17 CY

520 NMR 17 CZ

515 14B;17 DA

3.28 469 17 DB

4.41 453 18 DC

3.59 439 18 DD

3.74 465 18 DE

4.55 453 1H NMR (CD3OD): δ 8.19(m,1H), 8.05 (m, 1H), 7.87 (m, 1H),7.75(s, 1H); 7.70 (m, 1H); 7.15(m, 1H); 7.06 (m, 1H);7.00 (m, 1H); 5.70 (s,2H), 4.06(m, 2H); 3.02–3.21 (m, 2H),2.79 (s, 3H), 2.26 (m, 1H), 1.53(m,2H), 1.14 (m, 3H) 18 DF

4.81 482 20 DG

4.96 424 20 DH

4.91 424 20 DI

4.86 424 20 DJ

4.68 423 20AB;6C DK

4.61 390 20 DL

4.71 435 20 DM

4.35 427 20 DN

3.16 357 20 DO

4.264.66 390 20 DP

4.91 438 20 DQ

4.08 437 20 DR

4.21 332 20 DS

3.88 421 20 DT

4.58 453 20 DU

5.02 506 20 DV

3.44 385 20 DW

4.05 412 20 DX

4.31 406 20 DY

3.21 374 20 DZ

4.91 362 20 EA

3.78 450 20 EB

4.11 484 20 EC

4.36 406 20 ED

4.86 420 20 EE

420 20 EF

460 20 EG

420 20 EH

384 20 EI

434 20 EJ

396 20 EK

410 20 EL

434 20 EM

420 20 EN

5.15 406 21 EO

4.78 415 21 EP

4.91 424 21 EQ

4.55 400 21 ER

4.51 381 21 ES

4.78 370 21 ET

4.65 401 21 EU

5.18 424 21 EV

4.61 386 21 EW

4.58 386 21 EX

4.65 401 21 EY

4.88 390 21 EZ

4.61 356 21 FA

4.95 406 21 FB

4.85 390 21 FC

4.78 370 21 FD

4.18 434 21 FE

4.98 384 21 FF

432 21 FG

4.28 388 23 FH

3.38 388 23 FI

3.48 460 24 FJ

3.95 446 24 FK

4.01 431 25 FL

3.78 430 26 FM

393 27 FN

3.75 440 28A;9C;10ABD FO

4.61 469 28 FP

503 28 FQ

3.78 485 29A;9C;10ABD FR

4.28 514 29 FS

593 29 FT

5.18 526 30 FU

4.05 479 1HNMR(400 MHz, CD3OD): d8.05–8.03 (m, 1H), 7.95–7.93 (m 1H),7.84–7.80(m, 1H), 7.57–7.53 (m, 1H),7.39 (m, 1H), 7.25–7.20(m, 1H),7.11–7.04 (m,2H), 5.63 (m, 2H), 3.81–3.78(m, 4H), 3.27–3.14 (m,2H),2.21–2.17 (m, 5H),1.57–1.53 (m, 1H),1.45 1.43 (m, 1H). 14; 31 FV

4.18 493 1HNMR(400 MHz, CD3OD): d8.01–7.99 (m, 1H), 7.92–7.90 (m, 1H),7.79 7.75(m, 1H), 7.52–7.48 (m, 1H),7.34 (s, 1H), 7.22–7.18(m, 1H),7.11–7.03 (m,2H), 5.63 (m, 2H), 4.51–4.46 (m, 1H), 3.91–3.88 (m,1H),3.71–3.64 (m, 1H),3.27–3.12 (m, 2H), 2.30–2.13 (m, 4H), 1.95–1.93(m,1H), 1.55 1.53 (m, 1H), 1.45–1.43 (m, 1H), 1.33 1.31 (m, 3H). 14; 31FW

3.64 495 1HNMR(400 MHz, CD3OD): d7.90–7.88 (m, 1H), 7.73–7.71 (m, 1H),7.60 7.56(m, 1H), 7.34–7.30 (m, 2H),7.16 6.99 (m, 3H), 5.51 (s,2H),3.82–3.80 (m,4H), 3.71–3.69 (m, 4H), 3.25–3.12 (m, 2H), 2.17–2.14(m,1H), 1.55 1.52 (m,1H), 1.47–1.43 (m, 1H). 14; 31 FX

3.31 508 1H NMR (CD3OD): δ 8.08–8.06 (m, 2H), 7.85–7.81 (m, 1H),7.63–7.57(m, 2H), 7.23–7.18 (m, 1H),7.10–7.03 (m, 2H), 5.63(s, 2H),4.28–4.14(m, 4H), 3.58–3.50 (m,4H), 3.27–3.14 (m,2H), 3.00 (s, 3H),2.25–2.18 (m, 1H), 1.56–1.53(m, 1H), 1.45–1.42(m, 1H). 14; 31 FY

4.45 494 31 FZ

4.48 510 31 GA

3.78 523 31 GB

4.01 454 31 GC

3.58 509 31 GD

4.05 519 30 GE

522 34 GF

506 34 GG

532 34 GH

506 34 GI

548 34 GJ

534 34 GK

532 34 GL

4.76 356 1H NMR (CD3CN): d 7.6–7.4 (m,5H); 7.3 (m, 1H); 6.95 (m, 3H);5.2(s, 2H); 3.7 (s, 3H); 3.3–3.1(m, 2H); 2.4 (m, 1H); 1.65–1.55(m, 2H). 35GM

327 35A;3A; 2B GN

341 35A;2B GO

6.06 397 35A GP

355 35A;3A;2B; 9C GQ

3.91 325 35A;3A;2B; 8C GR

3.86 435 1H NMR (CDCl3): d 7.67 (m,2H), 7.09–6.97 (m, 3H), 6.88 (m,2H),6.72 (m, 1H), 3.81 (s, 3H),3.62 (s, 3H), 3.34 (m, 1H), 3.02(m, 1H),2.41–2.37 (m,1H), 1.65–1.62 (m, 1H), 1.55–1.52 (m, 1H) 36ABCE GS

4.11 449 1H NMR (CDCl3): d 7.50 (m,2H), 7.14–7.17 (m, 3H), 6.92 (m,2H),6.57 (m, 1H), 3.86 (s, 3H),3.73 (m, 1H), 3.70 (s, 3H), 3.10(s, 3H),3.01–2.97 (m,1H), 1.71–1.59 (m, 2H), 1.27–1.24 (m, 1H). 36ABCDF GT

4.06 449 1H NMR (CD3OD): d 7.65–7.63 (m, 2H), 7.10–7.08 (m,2H),6.97–6.94 (m, 4H), 4.00 (q,2H), 3.82 (s, 3H), 3.16–2.98 (m,2H),2.27–2.24 (m, 1H), 1.53–1.49 (m, 2H), 1.06 (m, 3H) 37A GU

4.36 463 1H NMR (CD3OD): d 7.45–7.42 (m, 2H), 7.20–7.18 (m,2H),7.02–6.96 (m, 4H), 4.06 (q,2H), 3.87 (s, 3H), 3.23–3.09 (m,2H), 3.12(s, 3H), 2.32–2.28 (m, 1H), 1.57–1.54 (m, 2H),1.14 (m, 3H) 37B GV

4.71 530 38 GW

4.41 515 38 GX

449 1HNMR(300 MHz, DMSO), d10.74(s, 1H), 8.79(s, 1H), 8.07(m,1H),7.95(m, 1H), 7.74–7.59(m,1H), 7.58–7.53(m,1H), 7.51(s, 1H), 7.05(m,2H),6.96(m, 2H), 5.53(s, 2H), 3.63(m,1H), 3.46(s, 3H), 3.05(m, 1H),2.63(s, 3H), 1.97(s, 1H), 1.34(s, 3H),1.03(s, 3H) 39 GY

449 1HNMR(300 MHz, DMSO), d10.42(s, 1H), 8.71(s, 1H), 8.08(m,1H), 7.95(m, 1), 7.75–7.68(m, 1H), 7.58–7.48 (m, 2H), 7.10(m, 2H), 7.02 (m, 2H),5.55(s, 2H), 3.39 (s, 3H), 3.21(m, 1H), 2.77 (m, 1H), 2.64(s, 3H), 1.43(s, 1H), 1.32 (s, 3H),1.25(s, 3) 39 GZ

434 39A;10B HA

4.56 410 1; 2B;20 HB

4.41 468 1; 2B;20 HC

4.46 421 1; 2B;20 HD

4.21 387 1; 2B;20 HE

4.014.214.41 376 1; 2B;20 HF

4.66 406 1; 2B;20 HG

4.66 406 1; 2B;20 HH

4.21 360 1; 2B;20 HI

4.16 372 1; 2B;20 HJ

4.31 386 1; 2B;20 HK

4.81 424 1; 2B;20 HL

2.752.96 343 1; 2B;20 HM

4.31 356 1; 2B;20 HN

4.31 386 1; 2B;20 HO

4.06 342 1H NMR (CD3CN): d 7.65–7.4(m, 5H); 7.35 (m, 1H); 7.0 (m,3H);5.19 (m, 2H); 3.7 (s, 3H);2.4 (m, 1H); 2.05 (m,); 1.85(m,1H) 1; 2B;20 HP

4.56 390 1; 2B;20 HQ

4.86 478 1; 2B;20 HR

3.91 370 1; 2B;20 HS

3.96 318 1; 2B;20 HT

4.61 348 1; 2B;20 HU

2.91 343 1; 2B;20 HV

3.76 304 1; 2B;20 HW

4.11 320 1; 2B;20 HX

4.31 396 1; 2B;20 HY

3.76 306 1; 2B;20 HZ

4.36 376 1; 2B;20 IA

3.764.01 360 1; 2B;20 IB

4.11 342 1; 2B;20 IC

4.66 410 1; 2B;20 ID

3.31 407 1H NMR (CD3CN): d 8.45 (d,1H); 8.25–8.05 (m, 3H); 7.95 (m,1H);7.25 (m, 1H); 7.05–6.95(m, 3H); 5.85 (m, 2H); 3.6 (s. 3H);3.0 (s, 3H);2.55 (m, 1H); 2.0 (m,1H); 1.8 (m, 1H). 1; 2B;20 IE

4.51 410 1; 2B;20 IF

4.16 387 1; 2B;20 IG

2.86 392 1H NMR (CD3CN): d 8.45 (m,1H); 8.25–8.05 (m, 3H); 7.95 (m,1H);7.25 (m, 1H); 7.05–6.95(m, 3H); 5.85 (m, 2H); 3.0 (s, 3H);2.55 (m, 1H);2.0 (m, 1H);1.8 (m, 1H) 1; 2B;20 IH

4.18 387 1; 2B;20AB;21 II

4.35 378 1; 2B;20AB;21 IJ

4.31 356 1; 2B;20AB;21 IK

4.11 342 1; 2B;20AB;21 IL

3.78 370 1; 2B;20AB;21 IM

372 1; 2B;20AB;21 IN

4.11 342 1; 2B;20AB;21 IO

3.88 358 1; 2B;20AB;21 IP

3.81 353 1; 2B;20AB;21 IQ

3.98 373 1; 2B;20AB;21 IR

4.01 373 1; 2B;20AB;21 IS

3.84 353 1; 2B;20AB;21 IT

4.31 342 1; 2B;20AB;21 IU

3.91 328 1; 2B;20AB;21 IV

4.11,4.36 392 1; 2B;20AB;21 IW

4.95 384 10ABC IX

434 10ABC IY

434 10ABC IZ

3.91 552 1H NMR(400 MHz, CD3OD): d8.42–8.32 (m, 3H), 8.12–8.06(m, 3H),7.92 7.88 (m, 1H),7.72–7.68 (m, 3H), 7.177.15 (m, 2H), 7.09–7.07 (m,2H),5.85 (s, 2H), 3.97–3.88 (m,1H), 3.52–3.35 (m, 4H),3.20–3.08 (m, 2H),2.02–1.98(m, 1H), 1.88–1.82 (m, 1H),1.77 1 10ABD JA

4.21 565 1H NMR(400 MHz, CD3OD): d8.35–8.28 (m, 3H), 8.13–8.11(m, 2H),8.04 7.98 (m, 1H),7.86–7.81 (m, 1H), 7.677.65 (m, 3H), 7.20–7.17 (m,2H),7.12 7.10 (m, 2H), 5.81 (s, 2H),3.80–3.43 (m, 5H),3.14–3.11 (m, 1H),3.03–2.97 (m, 1H), 2.92–2.80(m, 6H), 2.36 2 10ABD JB

4.21 565 10ABD JC

3.64 490 1H NMR(400 MHz, CD3OD): d8.46–8.44 (m, 1H), 8.24–8.14(m, 3H),8.00 7.96 (m, 1H),7.19–7.06 (m, 4H), 5.85(s, 2H), 4.38–4.35 (m,1H),3.65–3.36 (m, 4H),3.33–3.27 (m,), 3.15–2.99(m, 2H), 1.96–1.78 (m,3H), 1.54–1.45(m, 5H). 10ABD JD

3.61 553 1H NMR(400 MHz, CD3OD): d8.41–8.33 (m, 3H), 8.12–8.10(m, 3H),7.93 7.90 (m, 1H),7.71–7.69 (m, 3H), 7.187.10 (m, 4H), 5.85 (s,2H),3.63–3.49 (m, 2H), 3.16–3.09 (m, 7H), 2.92–2.78 (m, 6H), 2.03–2.01(m,1H), 1.53 1.51 (m, 1H),1.45–1.42 (m, 1H). 10ABD JE

3.94 633 10ABD JF

3.81 517 10ABD JG

3.48 490 10ABD JH

3.11 409 1H NMR (CD3OD): d 8.44(m, 1H); 8.16 (m, 3H); 7.97 (m,1H); 7.27(m, 2H); 7.09 (m, 2H);5.85 (s, 2H); 3.20 (m, 2H);3.01 (s, 3H);2.17–2.13(m, 1H), 1.56–1.52 (m, 1H),1.48–1.45 (m, 1H) 10ABD JI

3.21 476 10ABD JJ

3.21 476 10ABD JK

3.11 406 10ABD JL

4.01 552 10ABD JM

3.91 439 12;10AB;2C;3A; 3C JN

4.98 514 1H NMR(400 MHz, CD3OD): d8.4 (d, 1H); 8.39 (s, 1H); 8.35(m,1H); 8.1 (m, 2H); 8.05 (m, 1H); 7.9(m, 2H); 7.7 (m, 2H); 7.22 (m.1H);6.9–7.0 (m, 2H);5.9(s, 2H); 3.1 (br.2H); 3.0 (br, 3H); 2.8 (br,3H); 2.9(m, 1H);1.5 (m, 1H); 1.39 (m, 1H). 12;10ABD JO

4.55 452 12;10ABD JP

3.18 452 12;10ABD JQ

4.05 501 12;10ABD JR

3.68 508 1HNMR(400 MHz, CD3OD): d8.44–8.42 (m, 1H), 8.24–8.14 (m, 3H),7.99–7.95(m, 1H), 7.27–7.21 (m,1H), 7.07–6.98 (m, 2H),5.91 (s, 2H),4.43–4.37 (m, 1H),3.67–3.63 (m, 2H), 3.49–3.40 (m, 2H), 3.33–3.27(m, ),3.16–3.03 (m, 2H),1.94–1.86 (m, 2H),1.54–1.46 (m, 6H). 12;10ABD JS

3.48 507 12;10ABD JT

3.61 535 12;10ABD JU

3.61 603 12;10ABD JV

584 12;10ABD JW

3.58 439 1HNMR(400 MHz, CD3OD): d7.99–7.97 (m, 1H), 7.90–7.88 (m, 1H),7.807.77 (m, 1H), 7.56–7.52 (m,1H), 7.28 (s, 1H), 7.20–7.16 (m,1H),7.10–7.03 (m, 2H),5.58 (s, 2H), 3.27–3.13 (m, 5H),2.18–2.13 (m, 1H),1.56–1.54(m, 1H), 1.45–1.43 (m, 1H). 14; 31 JX

2.25 434 2AB; 6 JY

2.6 474 2AB; 6 JZ

2.3 446 2AB; 6 KA

2.5 468 2AB; 6 KB

2.3 475 2AB; 6 KC

1.95 406 2AB; 6 KD

2.55 496 2AB; 6 KE

2.45 482 2AB; 6 KF

2.6 496 2AB; 6 KG

2.5 500 2AB; 6 KH

1.85 483 2AB; 6 KI

1.85 483 2AB; 6 KJ

2.15 420 2AB; 6 KK

2.6 496 2AB; 6 KL

1.8 475 2AB; 6 KM

4.01 435 1; 7ABC; 8AB KN

2.4 421 1; 7ABC; 8AB KO

2.55 435 1; 7ABC; 8AB KP

2.7 449 1; 7ABC; 8AB KQ

3.06 393 1; 7ABC; 8A KR

4.16 341 1H NMR (CD3CN): d 7.65–7.4(m, 5H); 7.35 (m, 1H); 6.95 (m,3H);6.15 (br s, 1H); 5.95 (br s,1H); 5.2 (s, 2H); 3.4–3.4(m, 2H); 2.35 (m,1H); 1.6 (m, 1H);1.47 (m, 1H). 35A; 7ABC; 8AC KS

3.91 453 1H NMR (CD3OD): d 8.19 (m, 1H),8.05 (m, 1H), 7.87 (m, 1H),7.75(s, 1H); 7.70 (m, 1H); 7.15 (m,1H); 7.06 (m, 1H); 7.00 (m, 1H);5.70(s, 2H), 4.06 (m, 2H); (s,3H), 3.02–3.21 (m, 2H), 2.79(s, 3H), 2.26 (m,1H),1.53 (m, 2H), 1.14 (m, 3H) 38 KT

3.51 327 1H NMR (CD3CN): d 7.65–7.45(m, 5H); 7.4 (m, 2H); 7.1 (m,2H);6.0 (br s, 1H); 5.65 (br s, 1H);2.6 (m, 1H); 1.85 (m, 1H);1.7 (m,1H) 4A;2ABC;3 KU

4.26 356 1H NMR (CD3CN): d 7.62–7.4(m, 5H); 7.3 (m, 2H); 7.0 (m, 2H);5.2(s, 2H); 4.2 (m, 2H); 2.6 (m,1H); 2.05 (m, 1H); 2.85 (m,1H), 1.25 (m,3H). 4 KV

4.06 341 1H NMR (CD3CN: D2O (1:1)):d 7.40 7.29 (m, 5H), 7.12 (m,2H),6.88 (m, 2H), 5.03 (s, 2H), 3.08–2.85 (m, 2H), 2.06–2.02 (m,1H),1.50–1.46 (m, 1H),1.38–1.35 (m, 1H) 7ABC;8AC KW

3.21 303 1H NMR (CD3OD): d 7.18 (m,2H), 6.86 (m, 2H), 4.61 (s,2H),3.23–3.09 (m, 2H), 2.16–2.13 (m, 1H), 1.81 (m,3H), 1.55–1.51 (m,1H),1.47–1.44 (m, 1H) 7ABC;8AC KX

4.65 468 1H NMR(400 MHz, CD3OD): d8.43–8.33 (m, 3H), 8.12–8.09 (m,3H),7.94 7.90 (m, 1H), 7.73–7.68 (m, 3H), 7.28 7.26 (m,2H), 7.11–7.09 (m,2H),5.85(s, 2H), 3.27–3.12 (m, 2H),2.16–2.12 (m, 1H), 1.56–1.53 (m, 1H),1.47 1.44 (m, 1H) 7ABC;8AC KY

3.85 538 1H NMR(400 MHz, CD3OD): d8.40–8.30 (m, 3H), 8.12–8.04 (m,3H),7.90 7.87 (m, 1H), 7.69–7.67 (m, 3H), 7.18 7.06 (m,4H), 5.84 (s, 2H),4.35–4.28(m, 1H), 3.63–3.37 (m, 3H), 3.22–2.96 (m, 3H), 1.90–1.66 (m,3H),1.54 1.51 (m, 1H), 1.46–1.42(m, 1H). 9; 10ABD KZ

3.78 537 1HNMR(400 MHz, CD3OD): d8.46–8.49 (m, 3H), 8.18–8.09 (m,3H),8.00 7.96 (m, 1H), 7.79–7.70 (m, 3H), 7.17 7.09 (m,4H), 5.87 (s, 2H),3.85–3.39(m, 5H), 3.12–3.03 (m, 2H), 2.28–2.16 (m, 1H), 2.00–1.95 (m,2H),1.54 1.35 (m, 2H). 9; 10ABD LA

3.81 538 1H NMR(400 MHz, CD3OD): d8.39–8.29 (m, 3H), 8.12–8.03 (m,3H),7.90 7.84 (m, 1H), 7.69–7.67 (m, 3H), 7.17 7.06 (m,4H), 5.83 (s, 2H),4.30–4.27(m, 1H), 3.62–3.39 (m, 3H), 3.26–3.08 (m, 3H), 2.01–1.63 (m,3H),1.55 1.45 (m, 1H), 1.37–1.29 (m, 1H). 9; 10ABD LB

4.91 496 1H NMR(400 MHz, CD3OD): d8.46–8.35 (m, 3H), 8.16–8.10(m,3H)7.97–7.94 (m, 1H),7.77–7.71 (m, 3H), 7.147.08 (m, 4H), 5.89 (s,2H), 3.07(s, 2H), 2.96 (s, 3H), 2.78 (s, 3H),1.93–1.86 (m, 1H),1.53–1.50 (m, 1H), 1.36 1.33 (m, 1H) 9; 10ABD LC

3.84 420 9; 10ABD LD

4.66 327 6A; 8A LE

326 5AB;8A; 3B;2B LF

4.76 355 6A; 9C LG

497 43 LH

456 15 LI

502 30B LJ

569 12ABC;13, 33,3 LK

597 12ABC;13, 33,3 LL

371 15 LM

493 14, .31

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications that are within the spirit and scopeof the invention, as defined by the appended claims.

1. A method for treating inflammatory disorder associated with TACE(TNF-α) and/or MMP, consisting of Crohn's disease and colitis, osteo andrheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,multiple sclerosis, osteoporosis, soriasis and atopidermatitiscomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate or isomer thereof,wherein: M is —(C(R³⁰)(R⁴⁰))_(m)—, wherein m is 1; T is selected fromthe group consisting of R²¹-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—OR³, —C(O)R⁴, —C(O)OR³, —C(O)NR²⁴R²⁵, —C(O)NR²⁴OR³, —C(O)SR³, —NR²⁴R²⁵,—NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵, —NR²⁵C(O)NR²⁴OR³, —SR³,—S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN, —P(O)(R²⁴)(OR²⁴),—P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)-AA-NR²⁴R²⁵ and—C(O)-AA-NR²⁵OR³, wherein each of the cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of T isindependently unsubstituted or substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group of R²⁰moieties below; V is selected from the group consisting of alkyl,R²¹-substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, heteroaryl, —OR³, —C(O)R⁴,—(CR²³R²⁴)_(n1)C(O)OR³, —C(O)NR²⁴R²⁵, —(CR²³R²⁴)_(n1)C(O)NR²⁵OR³,—C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵,—NR²⁵C(O)NR²⁴OR³, —SR³, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN,—P(O)(R²⁴)(OR²⁴), —P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)-AA-NR²⁴R²⁵and —C(O)-AA-NR²⁵OR³, wherein each of the cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of V isindependently unsubstituted or substituted with one to threeindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group of R²⁰moieties below; W is —(CH₂)—; X is unsubstituted phenyl; U is —O—(CH₂)—;n is 0 to 2; n1 is 0 to 2; x is 0 to 2; AA is

wherein R³¹ and R³² are the same or different and are each independentlyselected from the group consisting of H, alkyl, cycloalkyl, aryl,heteroaryl, —NR²⁴R²⁵, —(CH₂)₃NH(C═NH)—NH₂, —CH₂C(O)—NH₂, —CH₂C(O)OH,—CH₂SH, —CH₂S—SCH₂CH(NH₂)C(O)OH, —CH₂CH₂C(O)OH, —CH₂CH₂C(O)NH₂,—(CH₂)₄NH₂, —CH₂CH₂CH(OH)CH₂NH₂, —CH₂CH(CH₃)₂, —CH(CH₃)CH₂(CH₃),—CH₂CH₂SCH₃, —CH₂OH, —CH(OH)(CH₃),

or R³¹ and R³², together with the N to which R³¹ is attached and the Cto which R³¹ is attached, form a 5-membered ring which is unsubstitutedor independently substituted with a hydroxyl group; R¹ is selected fromthe group consisting of unsubstituted quinolyl, alkyl-substitutedquinolyl and aryl-substituted quinolyl; each R², R⁴ and R⁵ is the sameor different and each is independently selected from the groupconsisting of H, halo, alkyl, R²²-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—OR⁶, —C(O)R⁷, —C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵),—NR²⁴S(O)₂R²⁵, wherein each of the cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of R², R⁴and R⁵ is independently unsubstituted or substituted with one to fourindependently selected alkyl, R²²-substituted alkyl or R²² moietieswhich can be the same or different, each R²² moiety being independentlyselected from the group of R²² moieties below; each R³ is the same ordifferent and is independently selected from the group consisting of H,alkyl, R²²-substituted alkyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR⁶, —C(O)R⁷,—C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵) and —NR²⁴S(O)₂R²⁵,each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R³ is independentlyunsubstituted or substituted with one to four independently selectedalkyl, R²²-substituted alkyl or R²² moieties which can be the same ordifferent, each R²² moiety being independently selected from the groupof R²² moieties below; each R⁶ is independently selected from the groupconsisting of H, alkyl and —OCF₃; each R⁷ is independently selected fromthe group consisting of H, alkyl, heteroaryl and —CF₃; each R²⁰ isindependently selected from the group consisting of: alkyl,R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³,—C(O)OR³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)R⁵, —CF₃, —OCF₃,—C₂CF₃, —C(═NOH)R³, aryl, halo-substituted aryl, heteroaryl, cycloalkyl,heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵, wherein each of the aryl, halo-substituted aryl,heteroaryl, cycloalkyl and heterocycloalkyl groups of R²⁰ isindependently unsubstituted or substituted with one to fourindependently selected R²² moieties which can be the same or different,each R²² moiety being independently selected from the group of R²³moieties below, or two R²⁰ groups taken together with the carbon towhich both R²⁰ groups are attached is

R²¹ is one to three substituents independently selected from the groupconsisting of: —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³, —C(O)OR³,—C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —SO_(x)R⁵, —CF₃, —OCF₃, —CF₂CF₃,—C(═NOH)R³, R²³-substituted alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵; wherein each of the aryl, halo-substituted aryl,heteroaryl, cycloalkyl, and heterocycloalkyl groups of R²¹ isindependently unsubstituted or substituted with one to fourindependently selected R²³ moieties which can be the same or different,each R²³ moiety being independently selected from the group of R²³moieties below, or two R²¹ groups taken together with the carbon towhich both R²¹ groups are attached is

each R²² is independently selected from the group consisting of: halo,alkynyl, aryl, heteroaryl, —OR²⁴, —C₁–C₆ alkyl)—OR²⁴, —CN, —NO₂,—NR²⁴R²⁵, C(O)R²³, —C(O)OR²³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵,—S(O)_(x)R²³, —CF₃, —OCF₃, —CF₂CF₃, —C(═NOH)R²³, —N(R²⁴)S(O)_(x)R²⁵,—N(R²⁴)C(O)R²⁵, and —N(R²⁴)C(O)NR²⁴R²⁵, or two R²² groups taken togetherwith the carbon to which both R²² groups are attached is

each R²³ is independently selected from the group consisting of H,hydroxyl, halo and alkyl; each R²⁴ is independently selected from thegroup consisting of H and alkyl; each R²⁵ is independently selected fromthe group consisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl,cycloalkyl, heteroaryl, —NR²⁴R²⁴, —(C₁ to C₆ alkyl)NR²⁴N²⁴, —CF₃ and—S(O)_(x)R²³; each R²⁶ is independently selected from the groupconsisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl,heteroaryl and —NR³R⁴; R²⁷ is independently selected from the groupconsisting of heteroaryl, heterocycloalkyl and —NR²⁴R²⁵; R³⁰ isindependently selected from the group consisting of H and R²⁰substituent groups above; R⁴⁰ is independently selected from the groupconsisting of H and R²⁰ substituent groups above, or R³⁰ and R⁴⁰, takentogether with the carbon to which R³⁰ and R⁴⁰ are attached, is

with the proviso that at least one of V or T is selected from the groupconsisting of —C(O)—N(R³)(OR⁴), —C(O)OR³ and —C(O)NR²⁴R²⁵.
 2. A methodof treating rheumatoid arthritis, osteoarthritis, periodontal disease,cancer or osteoporosis in a subject comprising: administering to thesubject in need of such treatment a therapeutically effective amount ofa compound of Formula (I):

or a pharmaceutically acceptable salt, solvate or isomer thereof,wherein: M is —(C(R³⁰)(R⁴⁰))_(m)—, wherein m is 1; T is selected fromthe group consisting of R²¹-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—OR³, —C(O)R⁴, —C(O)OR³, —C(O)NR²⁴R²⁵, —C(O)NR²⁴OR³, —C(O)SR³, —NR²⁴R²⁵,—NR²⁵C(O)R⁴, —NR²⁵O(O)OR³, —NR²⁵C(O)NR²⁴R²⁵, —NR²⁵C(O)NR²⁴OR³, —SR³,—S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN, —P(O)(R²⁴)(OR²⁴),—P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)-AA-NR²⁴R²⁵ and—C(O)-AA-NR²⁵OR³, wherein each of the cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of T isindependently unsubstituted or substituted with one to fiveindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group of R²⁰moieties below; V is selected from the group consisting of alkyl,R²¹-substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, heteroaryl, —OR³, —C(O)R⁴,—(CR²³R²⁴)_(n1)C(O)OR³, —C(O)NR²⁴R²⁵, —(CR²³R²⁴)_(n1)C(O)NR²⁵OR³,—C(O)SR³, —NR²⁴R²⁵, —NR²⁵C(O)R⁴, —NR²⁵C(O)OR³, —NR²⁵C(O)NR²⁴R²⁵,—NR²⁵C(O)NR²⁴OR³, —SR³, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)NR²⁵OR³, —CN,—P(O)(R²⁴)(OR²⁴), —P(O)(OR²⁴)(OR²⁴), —C(R⁴)(═N(OR³)), —C(O)-AA-NR²⁴R²⁵and —C(O)-AA-NR²⁵OR³, wherein each of the cycloalkyl, heterocycloalkyl,cycloal kenyl, heterocycloalkenyl, aryl and heteroaryl groups of V isindependently unsubstituted or substituted with one to threeindependently selected R²⁰ moieties which can be the same or different,each R²⁰ moiety being independently selected from the group of R²⁰moieties below; W is —(CH₂)—; X is unsubstituted phenyl; U is —O—(CH₂)—;n is 0 to 2; n1 is 0 to 2; x is 0 to 2; AA is

wherein R³¹ and R³² are the same or different and are each independentlyselected from the group consisting of H, alkyl, cycloalkyl, aryl,heteroaryl, —NR²⁴R²⁵, —(CH₂)₃NH(C═NH)NH₂, —CH₂C(O)NH₂, —CH₂C(O)OH,—CH₂SH, —CH₂S—SCH₂CH(NH₂)C(O)OH, —CH₂CH₂C(O)OH, —CH₂CH₂C(O)NH₂,—(CH₂)₄NH₂, —CH₂CH₂CH(OH)CH₂NH₂, —CH₂CH(CH₃)₂, —CH(CH₃)CH₂(CH₃),—CH₂CH₂SCH₃, —CH₂OH, —CH(OH)(CH₃),

or R³¹ and R³², together with the N to which R³¹ is attached and the Cto which R³¹ is attached, form a 5-membered ring which is unsubstitutedor independently substituted with a hydroxyl group; R¹ is selected fromthe group consisting of unsubstituted quinolyl, alkyl-substitutedquinolyl and aryl-substituted quinolyl; each R², R⁴ and R⁵ is the sameor different and each is independently selected from the groupconsisting of H, halo, alkyl, R²²-substituted alkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl,—OR⁶, —C(O)R⁷, —C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵),—NR²⁴S(O)₂R²⁵, wherein each of the cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of R², R⁴and R⁵ is independently unsubstituted or substituted with one to fourindependently selected alkyl, R²²-substituted alkyl or R²² moietieswhich can be the same or different, each R²² moiety being independentlyselected from the group of R²² moieties below; each R³ is the same ordifferent and is independently selected from the group consisting of H,alkyl, R²²-substituted alkyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR⁶, —C(O)R⁷,—C(O)OR⁶, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —N(═C—O—NR²⁴R²⁵) and —NR²⁴S(O)₂R²⁵,each of the cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl and heteroaryl groups of R³ is independentlyunsubstituted or substituted with one to four independently selectedalkyl, R²²-substituted alkyl or R²² moieties which can be the same ordifferent, each R²² moiety being independently selected from the groupof R²² moieties below; each R⁶ is independently selected from the groupconsisting of H, alkyl and —OCF₃; each R⁷ is independently selected fromthe group consisting of H, alkyl, heteroaryl and —CF₃; each R²⁰ isindependently selected from the group consisting of: alkyl,R²¹-substituted alkyl, —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³,—C(O)OR³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —S(O)_(x)R⁵, —CF₃, —OCF₃,—CF₂CF₃, —C(═NOH)R³, aryl, halo-substituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵, wherein each of the aryl, halo-substituted aryl,heteroaryl, cycloalkyl and heterocycloalkyl groups of R²⁰ isindependently unsubstituted or substituted with one to fourindependently selected R²² moieties which can be the same or different,each R²² moiety being independently selected from the group of R²³moieties below, or two R²⁰ groups taken together with the carbon towhich both R²⁰ groups are attached is

R²¹ is one to three substituents independently selected from the groupconsisting of: —OR³, halo, —CN, —NO₂, —NR²⁴R²⁵, —C(O)R³, —C(O)OR³,—C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵, —SO_(x)R⁵, —CF₃, —OCF₃, —CF₂CF₃,—C(═NOH)R³, R²³-substituted alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, —N(R²⁵)S(O)_(x)R⁵, —N(R²⁵)C(O)R⁵, and—N(R²⁵)C(O)NR²⁴R²⁵; wherein each of the aryl, halo-substituted aryl,heteroaryl, cycloalkyl, and heterocycloalkyl groups of R²¹ isindependently unsubstituted or substituted with one to fourindependently selected R²³ moieties which can be the same or different,each R²³ moiety being independently selected from the group of R²³moieties below, or two R²¹ groups taken together with the carbon towhich both R²¹ groups are attached is

each R²² is independently selected from the group consisting of: halo,alkynyl, aryl, heteroaryl, OR²⁴, —(C₁–C₆ alkyl)—OR²⁴, —CN, —NO₂,—NR²⁴R²⁵, —C(O)R²³, —C(O)OR²³, —C(O)NR²⁴R²⁵, —S(O)_(x)NR²⁴R²⁵,—S(O)_(x)R²³, —CF₃, —OCF₃, —CF₂CF₃, —C(═NOH)R²³, —N(R²⁴)S(O)_(x)R²⁵,—N(R²⁴)—C(O)R²⁵, and —N(R²⁴)C(O)NR²⁴R²⁵, or two R²² groups takentogether with the carbon to which both R²² groups are attached is

each R²³ is independently selected from the group consisting of H,hydroxyl, halo and alkyl; each R²⁴ is independently selected from thegroup consisting of H and alkyl; each R²⁵ is independently selected fromthe group consisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl,cycloalkyl, heteroaryl, —NR²⁴R²⁴, —(C₁ to C₆ alkyl)NR²⁴N²⁴, —CF₃ and—S(O)_(x)R²³; each R²⁶ is independently selected from the groupconsisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl,heteroaryl and —NR³R⁴; R²⁷ is independently selected from the groupconsisting of heteroaryl, heterocycloalkyl and —NR²⁴R²⁵; R³⁰ isindependently selected from the group consisting of H and R²⁰substituent groups above; R⁴⁰ is independently selected from the groupconsisting of H and R²⁰ substituent groups above, or R³⁰ and R⁴⁰, takentogether with the carbon to which R³⁰ and R⁴⁰ are attached, is

with the proviso that at least one of V or T is selected from the groupconsisting of —C(O)—N(R³)(OR⁴), —C(O)OR³ and —C(O)NR²⁴R²⁵.